A class of cyclic compounds, their preparation methods and pharmaceutical uses

Abstract

The present invention discloses a class of spirocyclic compounds, their preparation methods and pharmaceutical applications. Specifically, the present invention discloses the compounds shown in formula (I), their optical isomers or pharmaceutically acceptable salts, and their applications such as androgen receptor (AR) inhibitors, etc.

Description

A class of linked ring compounds and their preparation method and medical use

[0001] The present invention claims the following priority:

[0002] 1) Application number CN 202311201930.9, application date September 15, 2023;

[0003] 2) Application number CN 202311547952.0, filing date November 17, 2023;

[0004] 3) Application number CN 202311588615.6, filing date November 24, 2023;

[0005] 4) Application number CN 202311698673.4, application date December 11, 2023;

[0006] 5) Application number CN 202410239612.X, application date March 1, 2024.

[0007] 6) Application number CN 202410546567.2, application date April 30, 2024;

[0008] 7) Application number CN 202410734815.6, application date June 6, 2024;

[0009] 8) Application number CN 202411040155.8, application date July 30, 2024;

[0010] 9) Application number CN 202411238360.5, application date September 4, 2024. Technical Field

[0011] The present invention belongs to the field of medicinal chemistry, and in particular relates to a class of linked ring compounds, a preparation method thereof, and medical applications thereof. Background Art

[0012] Prostate cancer is an androgen-dependent tumor. Androgens can bind to androgen receptors (AR) and stimulate the growth of prostate cancer cells and disease progression. Endocrine therapy is one of the conventional treatment methods. For example, the standard treatment for advanced PCa is mainly androgen deprivation therapy (ADT), such as surgical castration (bilateral orchiectomy) or medical castration (such as injection of Noradrena). ADT therapy has a significant effect in the early stages of treatment, but as the disease progresses, AR mutates, and the mutated AR is more sensitive to low levels of androgens, driving the disease to castration-resistant prostate cancer (CRPC). Almost all patients with advanced prostate cancer will eventually progress to CRPC after receiving endocrine therapy. In addition, up to 30% of prostate cancer patients will develop metastatic castration-resistant prostate cancer (mCRPC) within 10 years of initial treatment.

[0013] Currently, there are several oral drugs for the treatment of mCRPC, such as enzalutamide, apalutamide, and darolutamide. They mainly bind to the ligand-binding domain (AR-LBD) of the androgen receptor, thereby blocking the interaction between AR and DNA and thus exerting their efficacy. However, after 2-3 years of treatment with these drugs, patients are prone to drug resistance. The emergence of androgen receptor variants (AR-Vs) lacking the LBD region and mutations in the LBD region are two important mechanisms of drug resistance.

[0014] Compared to normal full-length AR, AR-Vs are truncated ARs. These splice variants lack the LBD during their formation, which results in the inability of androgens to bind to AR-Vs. However, because AR-Vs retain the N-terminal domain and DNA-binding domain (DBD), they can still bind to genomic DNA and regulate the expression of downstream target genes, exhibiting androgen-independent constitutive activity, which is one of the important mechanisms of ADT resistance and CRPC disease progression.

[0015] The development of inhibitors targeting the AR receptor NTD, with favorable physicochemical properties and druggability, is a new research direction for the treatment of prostate cancer. By modulating the AR N-terminal domain to inhibit the transcriptional function of the androgen receptor (AR) and block the androgen receptor transduction pathway, these inhibitors will have a profound and broad AR inhibitory effect. This has important clinical value in the treatment of AR-driven cancers such as prostate cancer, particularly androgen-independent androgen-resistant prostate cancer.

[0016] Summary of the Invention

[0017] In one aspect of the present invention, the present invention provides a compound represented by formula (I), an optical isomer thereof and a pharmaceutically acceptable salt thereof,

[0018] in,

[0019] R1 is selected from H, halogen, OH, CN, NH2, H2N-S(=O)2-, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)(=NH)-, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Heteroalkyl or 3-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)(=NH)-, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;

[0020] R2, R3, R4 are independently selected from H, CN, F, Cl, Br, OH, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-, C 2-6 Alkenyl-O-, C 2-6 Alkenyl-S-, C 2-6 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S- or 4-6 membered heterocycloalkyl-NH-, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-, C 2-6 Alkenyl-O-, C 2-6 Alkenyl-S-, C 2-6 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6-cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S- and 4-6 membered heterocycloalkyl-NH- are optionally substituted with 1, 2 or 3 R;

[0021] R5, R6, R7 are independently selected from H, CN, F, Cl, Br, OH, NH2, C(=O)OH, C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-, C 2-6 Alkenyl-O-, C 2-6 Alkenyl-S-, C 2-6 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S-, 4-6 membered heterocycloalkyl-NH-, C 6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocycloalkyl, the C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-, C 2-6 Alkenyl-O-, C 2-6 Alkenyl-S-, C 2-6 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S-, 4-6 membered heterocycloalkyl-NH-, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;

[0022] m, n, and y are each independently selected from 0, 1, 2, 3, or 4;

[0023] L1 is selected from a single bond, -NH-, =N-, -O-, -C≡C-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -CH2-, -CH2CH2-, -OCH2-, C3- 6-membered cycloalkyl or 3-10-membered heterocycloalkyl, wherein -NH-, -CH2-, -CH2CH2-, -OCH2-, C 3-6 Cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1 or 2 R;

[0024] Selected from or And when Selected from When L1 is selected from =N- or 3-10 membered heterocycloalkyl;

[0025] L2 is selected from a single bond, -C≡C-, -CH=CH-, -(CR8R9)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR 10 -、-C 1-3 Alkyl-O-, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the -C 1-3 Alkyl-O-, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2 or 3 R;

[0026] L3 is selected from a single bond, -C≡C-, -CH=CH-, -(CR8R9)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR 10 -or-C 1-3 Alkyl-O-, the-C 1-3 Alkyl-O- is optionally substituted with 1, 2 or 3 R;

[0027] Moreover, L2 and L3 are not simultaneously selected from single bonds;

[0028] And, when L2 is selected from C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 When aryl or 5-10 membered heteroaryl, L3 is not selected from a single bond;

[0029] L4 is selected from -(CR8R9) X -, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2- or -NR 10 -;

[0030] R8 and R9 are independently selected from H, CN, F, Cl, Br, OH, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10Aryl, 5-10 membered heteroaryl, C 1-6 Heteroalkyl or 3-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;

[0031] R 10 Selected from H or C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Heteroalkyl or 3-10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R; x is selected from 1, 2 or 3;

[0032] Ring A is selected from C 4-10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl;

[0033] Ring B, Ring C, and Ring D are independently selected from C 4-10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo C 5-6 Cycloalkyl, benzo 5-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C 5-6 Cycloalkyl or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl;

[0034] R are independently selected from H, halogen, =O, =NR', OH, NH2, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkyl-S(=O)2-, (C 1-6 alkyl)2-P(=O)-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-OC(=O)-, C 1- 6-alkyl-C(=O)NH-, C 1-6 Alkyl-NH-C(=O)-, C 1-6 Alkyl-S(=O)NH-, C 1-6 Alkyl-S(=O)2NH-, C 1-6 Alkyl-NHS(=O)2-, C1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-, C 2-6 Alkenyl-O-, C 2-6 Alkenyl-S-, C 2-6 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3- 6-cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, C 3-6 Cycloalkyl-C(=O)-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S-, 4-6 membered heterocycloalkyl-NH- or C 6-10 Aryl-C 1-6 Alkyl-, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkyl-S(=O)2-, (C 1-6 alkyl)2-P(=O)-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-NH-C(=O)-, C 1-6 Alkyl-S(=O)NH-, C 1-6 Alkyl-S(=O)2NH-, C 1-6 Alkyl-NHS(=O)2-, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1- 6-alkyl-NH-, C 2-6 Alkenyl-O-, C 2-6 Alkenyl-S-, C 2-6 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, C 3-6 Cycloalkyl-C(=O)-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S-, 4-6 membered heterocycloalkyl-NH- or C 6-10 Aryl-C 1-6 Alkyl - optionally substituted with 1, 2 or 3 R';

[0035] R' is selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CHF2, CF3 and C 1-6Alkyl-S(═O)2-; the above-mentioned heteroaryl, heteroalkyl or heterocycloalkyl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C(═O), C(═O)O, C(═O)NH, S(═O), S(═O)2, P(═O), S(═O)2NH and N.

[0036] In some embodiments of the present invention, the above R are independently selected from H, halogen, OH, NH2, CN, =O、=NR'、C 1- 3 alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-S(=O)2-, (C 1-3 alkyl)2-P(=O)-, C 1-3 Alkyl-C(=O)O-, C 1-3 Alkyl-OC(=O)-, C 1-3 Alkyl-C(=O)NH-, C 1-3 Alkyl-NH-C(=O)-, C 1-3 Alkyl-S(=O)NH-, C 1-3 Alkyl-S(=O)2NH-, C 1-3 Alkyl-NHS(=O)2-, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-NH-, C 3-6 Cycloalkyl-C(=O)-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S-, 4-6 membered heterocycloalkyl-NH- or C 6-10 Aryl-C 1-3 Alkyl-, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-S(=O)2-, C 1-3 Alkyl-C(=O)O-, C 1-3 Alkyl-OC(=O)-, C 1-3 Alkyl-C(=O)NH-, C 1-3 Alkyl-NH-C(=O)-, C 1-3 Alkyl-S(=O)NH-, C 1-3 Alkyl-S(=O)2NH-, C 1-3 Alkyl-NHS(=O)2-, C 1- 3-alkyl-O-, C 1-3 Alkyl-S- or C 1-3 Alkyl-NH-, C3-6 Cycloalkyl-C(=O)-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S-, 4-6 membered heterocycloalkyl-NH- and C 6-10 Aryl-C 1-3 Alkyl- is optionally substituted with 1, 2 or 3 R's, and the remaining variables are as defined herein.

[0037] In some embodiments of the present invention, the above R are independently selected from H, F, Cl, B r ,I,OH,NH2,CN,=O,=NH,=N-CN, CH3, CH2F, CHF2, CF3, The remaining variables are as defined in the present invention.

[0038] In some embodiments of the present invention, the above R1 is selected from H, halogen, OH, CN, NH2, H2N-S(=O)2-, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-S(=O)2-, (C 1-6 alkyl)2-S(=O)=, (C 1-6 alkyl)2-P(=O)-, (C 1-6 alkyl)2-S(=O)=N-, C 1-6 Alkyl-S(=O)2NH-, C 1-6 Alkyl-NHS(=O)2-, C 1-6 Alkyl-NH-, C 1-6 Alkyl-S(=O)(=NH)-, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)(=NH)-, C 6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-S(=O)2-, (C 1-6 alkyl)2-S(=O)=, (C 1-6 alkyl)2-P(=O)-, (C 1-6 alkyl)2-S(=O)=N-, C1-6 Alkyl-S(=O)2NH-, C 1-6 Alkyl-NHS(=O)2-, C 1-6 Alkyl-NH-, C 1-6 Alkyl-S(=O)(=NH)-, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)(=NH)-, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R groups, and the remaining variables are as defined herein.

[0039] In some embodiments of the present invention, the above R1 is selected from H, F, Cl, Br, I, Me, CN, OH, NH2, H2N-S(=O)2-,

[0040] It is optionally substituted with 1, 2 or 3 R, and the remaining variables are as defined herein.

[0041] In some embodiments of the present invention, the above R1 is selected from H, F, Cl, Br, I, Me, CN, OH, NH2, H2N-S(=O)2-, The remaining variables are as defined in the present invention.

[0042] In some embodiments of the present invention, the above L1 is selected from a single bond, -CH2-, -NH-, =N-, -O-, -C≡C-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, The remaining variables are as defined in the present invention.

[0043] In some embodiments of the present invention, the above structural unit Selected from H, F, Cl, Br, I, H2N-S(=O)2-, The remaining variables are as defined in the present invention.

[0044] In some embodiments of the present invention, the above structural unit Selected from The remaining variables are as defined in the present invention.

[0045] In some embodiments of the present invention, the above structural unit Selected from H, F, Cl, Br, I, The remaining variables are as defined in the present invention.

[0046] In some embodiments of the present invention, the above structural unit Selected from H, F, Cl, Br, I, The remaining variables are as defined in the present invention.

[0047] In some embodiments of the present invention, R2, R3, and R4 are independently selected from H, CN, F, Cl, B r 、OH、NH2、C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-NH-, C 2-3 Alkenyl-O-, C 2-3 Alkenyl-S-, C 2-3 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3- 6-cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, oxirane-O- or azetidinyl-O-, the C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-NH-, C 2-3 Alkenyl-O-, C 2-3 Alkenyl-S-, C 2-3 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, oxirane-O-, and azetidinyl-O- are optionally substituted with 1, 2, or 3 R groups, and the remaining variables are as defined herein.

[0048] In some embodiments of the present invention, R2, R3, and R4 are independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me, The Me, It is optionally substituted with 1, 2 or 3 R, and the remaining variables are as defined herein.

[0049] In some embodiments of the present invention, R2, R3, and R4 are independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me, The remaining variables are as defined in the present invention.

[0050] In some embodiments of the present invention, the above R5, R6, and R7 are independently selected from H, CN, F, Cl, Br, OH, NH2, -COOH, -COOCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-NH-, C 2-3 Alkenyl-O-, C 2-3 Alkenyl-S-, C 2-3 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH- or oxirane-O-, the C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-NH-, C 2-3 Alkenyl-O-, C 2-3 Alkenyl-S-, C 2-3 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH- and oxirane-O- are optionally substituted with 1, 2 or 3 R groups, and the remaining variables are as defined herein.

[0051] In some embodiments of the present invention, the above R5, R6, and R7 are independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me, CH2F, CHF2, CF3, COOH, -COOMe, The remaining variables are as defined in the present invention.

[0052] In some embodiments of the present invention, R8 and R9 are independently selected from H, CN, F, Cl, Br, OH, NH2, Me or The remaining variables are as defined in the present invention.

[0053] In some embodiments of the present invention, the above R 10 Selected from H, Me, The remaining variables are as defined in the present invention.

[0054] In some embodiments of the present invention, the above L2 is selected from a single bond, -CH2-, -CH(CH3)-, -OCH2-, -C≡C-, -CH=CH-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NH-, The remaining variables are as defined in the present invention.

[0055] In some embodiments of the present invention, the above-mentioned L3 is selected from a single bond, -CH2-, -CH(CH3)-, -OCH2-, -C≡C-, -CH=CH-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2- or -NH-, and the remaining variables are as defined in the present invention.

[0056] In some embodiments of the present invention, the above-mentioned L2-L3 is selected from -CH2-, -CH2CH2-, -CH(CH3)-, -C≡C-, -CH=CH-, -O-, -OCH2-, -OCH2CH2-, -OCH(CH3)-, -OCH2OCH2-, -OCH2CH2O-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NH-, -CH2NH-,

[0057] In some embodiments of the present invention, the above L4 is selected from -CH2-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NH-, The remaining variables are as defined in the present invention.

[0058] In some embodiments of the present invention, the ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, oxazolyl, pyridazinyl, cyclobutanyl, oxetanyl, tetrahydropyranyl, 2-oxaspiro[3.3]heptane, 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide, tetrahydrofuranyl, azetidinyl, piperidinyl, 1,1-dioxidothiomorpholinyl, 2-thio-6-azaspiro[3.3]heptane-2,2-dioxyl, 2-imino-2λ6-thiaspiro[3.3]heptane 2-oxide, cyclohexanyl or 1-imino-1λ6-thiomorpholine 1-oxide, and the remaining variables are as defined herein.

[0059] In some embodiments of the present invention, the above structural unit Selected from The remaining variables are as defined in the present invention.

[0060] In some embodiments of the present invention, the above-mentioned ring B is selected from bicyclo[1.1.1]pentanyl, cyclobutanyl, cyclopentanyl, 2,6-diazaspiro[3.3]heptanyl, pyrazolyl, piperidinyl, thiazolyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, benzocyclopentanyl, benzocyclohexanyl, 1,2,3,4-tetrahydroquinolinyl, naphthyl, indolyl, isoindolyl, spiro[cyclopropane-1,3′-dihydroindolinyl]-2′-onyl, 3(2H)-pyridazinonyl, 2(1H)-pyridinonyl, isoquinolinyl or quinolin-2(1H)-onyl, and the remaining variables are as defined herein.

[0061] In some embodiments of the present invention, the above structural unit Selected from The remaining variables are as defined in the present invention.

[0062] In some embodiments of the present invention, the ring C is selected from azetidinyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl or spiro[cyclopropane-1,3′-dihydroindole]-2′-one, and the remaining variables are as defined in the present invention.

[0063] In some embodiments of the present invention, the above structural unit Selected from The remaining variables are as defined in the present invention.

[0064] In some embodiments of the present invention, the ring D is selected from phenyl, pyridyl, benzocyclopentyl, benzocyclohexyl, 1H-indazolyl, 2H-indazolyl or 1H-benzo[d]imidazolyl, and the remaining variables are as defined herein.

[0065] In some embodiments of the present invention, the above structural unit Selected from The remaining variables are as defined in the present invention.

[0066] The present invention also provides the following compounds, their optical isomers and pharmaceutically acceptable salts thereof, which are selected from:

[0067] The present invention also provides the following compounds, their optical isomers and pharmaceutically acceptable salts thereof, which are selected from:

[0068] In another aspect of the present invention, the present invention also provides the use of the aforementioned compound, its optical isomers or pharmaceutically acceptable salts thereof in the preparation of drugs for treating diseases related to androgen receptor (AR) activity or expression.

[0069] In some embodiments of the present invention, the above-mentioned androgen receptor (AR) activity or expression-related diseases are selected from prostate cancer, ovarian cancer, breast cancer, bladder cancer, pancreatic cancer, endometrial cancer, hepatocellular carcinoma, renal cell carcinoma, melanoma, mantle cell lymphoma, glioblastoma, salivary gland cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy and age-related macular degeneration.

[0070] Definition and Description

[0071] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0072] As used herein, the phrase "at least one" when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers may optionally be present, whether related or unrelated to those specifically identified elements.

[0073] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0074] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0075] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0076] "Pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, formulation aid, or vehicle commonly used in the art with therapeutic agents to form a "pharmaceutical composition" for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to the recipient at the dosage and concentration employed and is compatible with the other ingredients of the formulation. The pharmaceutically acceptable carrier is appropriate for the formulation being employed.

[0077] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.

[0078] A hyphen ("-") that is not between two letters or symbols indicates the site of attachment of a substituent. For example, C 1-6 Alkylcarbonyl - refers to a C-alkyl group attached to the rest of the molecule through a carbonyl group. 1-6 However, when the attachment point of the substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.

[0079] When the group valence bond is marked with a dotted line When, for example, In the example, the dashed line represents the point of attachment of the group to the rest of the molecule.

[0080] The term "substituted" or "substituted with" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted with" means that the atom may or may not be substituted. Unless otherwise specified, the type and number of substituents may be any based on chemical practicability.

[0081] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1, 2, or 3 R's, the group may optionally be substituted with 1, 2, or 3 R's, with each occurrence of R' being an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0082] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected, such as When L1 represents a single bond, it means that the structure is actually

[0083] When the substituents listed do not specify through which atom they are connected to the substituted group, such substituents can be bonded through any atom thereof. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0084] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -CH2O-, in which case -CH2O- can connect phenyl and cyclopentyl in the same direction as reading from left to right to form It is also possible to connect phenyl and cyclopentyl groups in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0085] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0086] Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, a "3-6 membered ring" refers to a "ring" having 3-6 atoms arranged around it.

[0087] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkyl, etc.; which can be monovalent (such as CH3), divalent (-CH2-) or polyvalent (such as ). C 1-6 Examples of alkyl groups include, but are not limited to, CH3, wait.

[0088] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-6 Alkenyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperyl, hexadienyl, and the like.

[0089] Unless otherwise specified, “C 2-3 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-3 Alkenyl includes C3 and C2 alkenyl; the C 2-3 Alkenyl groups can be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to wait.

[0090] The term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched chain alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatoms are selected from B, O, N, P and S, wherein the nitrogen, phosphorus and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -P(=O)-, -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C 1-6 In other embodiments, the heteroalkyl group is C 1-3 Heteroalkyl. The heteroatom or heteroatom group may be located at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule, but the term "alkoxy" is a customary expression and refers to those alkyl groups that are attached to the rest of the molecule through an oxygen atom. Examples of heteroalkyl groups include, but are not limited to, -OCH, -OCHCH, -OCHCHCH, -OCH(CH), -CH-CH-O-CH, -NHCH, -N(CH), -NHCHCH, -N(CH)(CHCH), -CH-CH-NH-CH, -CH-CH-N(CH)-CH, -SCH, -SCHCH, -SCHCHCH, -SCH(CH), -CH-S-CH-CH, -CH-CH-S-CH, -S(=O)-CH, -CH-CH-S(=O)-CH, And up to two heteroatoms may be consecutive, for example -CH2-NH-OCH3.

[0091] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0092] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-3 、C 1-2 、C 2-3 , C1, C2 and C3 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0093] Unless otherwise specified, the term “C 1-6 "Alkylamino" means an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an amino group. 1-6 Alkylamino groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylamino, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0094] Unless otherwise specified, the term “C 1-3 "Alkylamino" means an alkyl group containing 1 to 3 carbon atoms which is attached to the rest of the molecule via an amino group. 1-3 Alkylamino groups include C 1-3 、C 1-2 、C 2-3 , C1, C2 and C3 alkylamino, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, and the like.

[0095] Unless otherwise specified, the term “C 1-6 "Alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-6 Alkylthio includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylthio, etc.1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, and the like.

[0096] Unless otherwise specified, the term “C 1-3 "Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-3 Alkylthio includes C 1-3 、C 1-2 、C 2-3 , C1, C2 and C3 alkylthio, etc. 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, and the like.

[0097] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0098] Unless otherwise specified, the term "3-10 membered heterocyclyl" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S, P and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, phosphorus and sulfur atoms are independently optionally oxidized (i.e., C=O, P=O, NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocycles, cyclopentanes and bridged rings. In addition, with respect to this " 3-10 membered heterocyclic group ", heteroatoms can occupy the connection position of the heterocyclic group with the rest of the molecule. The 3-10 membered heterocyclic group includes 3-9 membered, 3-8 membered, 3-7 membered, 3-6 membered, 3-5 membered, 3-4 membered, 4-5 membered, 4-6 membered, 4-7 membered, 4-8 membered, 4-9 membered, 5-6 membered, 5-7 membered, 5-8 membered, 5-9 membered, 6-7 membered, 6-8 membered, 6-9 membered, 7-8 membered, 3 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered heterocyclic group etc. The example of 3-10 membered heterocyclic group includes but is not limited to azetidinyl, oxetanyl, thietanyl, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0099] Unless otherwise specified, the term "5-6 membered heterocyclyl" by itself or in combination with other terms means a saturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, fused and bridged rings. In addition, with respect to the "5-6 membered heterocyclic group", a heteroatom may occupy the position where the heterocyclic group is connected to the rest of the molecule. The 5-6 membered heterocyclic group includes 5-membered and 6-membered heterocyclic groups. Examples of 5-6 membered heterocyclic groups include, but are not limited to, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0100] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). 5-6 yuan of heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 yuan of heteroaryl includes 5 yuan and 6 yuan of heteroaryl. The example of the 5-6 yuan of heteroaryl includes but is not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0101] Unless otherwise specified, the term “C 6-10 "Aryl" by itself or in combination with other terms refers to a monocyclic or bicyclic aromatic ring system having six to ten carbon atoms. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl.

[0102] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0103] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0104] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0105] The solvent used in the present invention is commercially available.

[0106] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names.

[0107] The compounds disclosed in the present invention may have one or more chiral centers, each of which independently has an R configuration or an S configuration, or a cis-Cis-configuration, or a trans-Trans-configuration. The chiral centers of some compounds disclosed in the present invention are marked with *R, *S, R*, S, *Cis-, or *Trans-, indicating that the absolute configuration of the chiral center of the compound has not been identified, but the compound has been separated or chirally resolved and the chiral center is a chiral center with a single configuration, and the compound is a single-configuration enantiomer monomer, or a single-configuration diastereoisomer monomer, or a diastereoisomer mixture with a single configuration of the chiral center (for example: the configuration of other chiral centers has not been resolved), or a single-configuration monomer (for example, a single cis-configuration monomer, or a single trans-configuration monomer). When the absolute configuration (R configuration, S configuration, Cis-configuration, or Trans-configuration) of the chiral center of the compound disclosed in the present invention has not been identified, such compounds can be identified based on their corresponding nuclear magnetic resonance (NMR) spectra. 1 H-NMR, 31 The peak shape in the P-NMR spectrum or the retention time (RT or Rt) corresponding to the corresponding chromatographic column conditions (such as chromatographic column model, chromatographic column filling material, chromatographic column size, mobile phase, etc.) can be confirmed.

[0108] The present invention is explained in more detail in the following examples. However, it should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention in any way. The experimental methods in the following examples, unless otherwise specified, generally follow conventional conditions for such reactions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight. Unless otherwise stated, liquid ratios are by volume.

[0109] Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. DETAILED DESCRIPTION

[0110] The present application is described in detail below by way of examples, but this does not necessarily mean that there are any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0111] Unless otherwise specified, the experimental materials and reagents used in the following examples can be obtained from commercial channels.

[0112] In all embodiments, 1 H NMR, 13 C NMR, 19 F NMR and 31 The p NMR spectra were recorded using a Bruker Ascend 400 MHz NMR instrument and processed using Topspin software, with deuterated solvents acting as internal deuterium locks. 13 C NMR, 19 FNMR and 31 pNMR 1 H decoupling. Assignments were made based on well-defined chemical shifts / coupling patterns or on the basis of 2D Cosy, HMBC, HSQC, or NOESY experiments. Peak multiplicities were defined as: s singlet, d doublet, t triplet, q quartet, m multiplet, br broad, br.s broad singlet; coupling constants (J) were given to the nearest 0.1 Hz. Mass spectra were recorded using an Agilent 1260 (ESI) or Shimadzu LC-MS-2020 (ESI) or Agilent 6215 (ESI) mass spectrometer; reversed-phase preparative HPLC separations were performed using an Agilent 1290 UV-guided automated purification system (Xtimate C18 OBDTM 21.2*250mm 10μm column) or Gilson GX281 UV-guided automatic purification system (xBridge C18 OBDTM 19*250mm 10μm column) or Waters QDa-guided fully automated purification system (SunFire C18 OBD 29*250mm 10μm column). Unless otherwise specified, separations were performed using SepaFlash prepacked normal-phase silica gel columns (Sinopharm Chemical Reagent Co., Ltd.) and TLC analytical plates (Yantai Jiangyou Silica Gel Development Co., Ltd., model: HSGF254, size: 2.5×5cm). Eluent ratios were by volume.

[0113] The Chinese names of the reagents represented by chemical formulas or English abbreviations are as follows:

[0114] CD3OD represents deuterated methanol; DMSO-d6 represents deuterated dimethyl sulfoxide; Chloroform-d or CDCl3 represents deuterated chloroform; AcOH represents acetic acid; AlCl3 represents aluminum chloride; Aq represents an aqueous solution; N2 represents nitrogen; Ar represents argon; B2Pin2 represents diboronic acid pinacol ester; BBr3 represents boron tribromide; BH3 represents borane; (Boc)2O represents di-tert-butyl dicarbonate; Et3SiH represents triethylsilane; HATU represents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HOBt represents 1-hydroxybenzotriazole; TMA D represents N,N,N′,N′-tetramethylazodicarbonamide; K2CO3 represents potassium carbonate; KOAc represents potassium acetate; MeONa represents sodium methoxide; LDA represents lithium diisopropylamide; LiHMDS represents lithium bis(trimethylsilyl)amide; LiOH represents lithium hydroxide; m-CPBA represents m-chloroperbenzoic acid; Na2CO3 represents sodium carbonate; NaBH4 represents sodium borohydride; NaCl represents sodium chloride; NaHCO3 represents sodium bicarbonate; NaOH represents sodium hydroxide; Na2SO4 represents sodium sulfate; NBS represents N-bromosuccinimide; NCS represents N-chlorosuccinimide; NIS represents N-iodosuccinimide; Oxone represents represents potassium peroxymonosulfonate; n-BuLi represents n-butyllithium; NH4Cl represents ammonium chloride; NMP represents N-methyl-2-pyrrolidone; PBr3 represents phosphorus tribromide; Pd(dppf)Cl2 or PdCl2(dppf) represents 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium(0); Pd(OAc)2 represents palladium acetate; conc. represents concentrated; (COCl)2 represents oxalyl chloride; Cs2CO3 represents cesium carbonate; CuCl represents cuprous chloride; CuI represents cuprous iodide; DCM represents dichloromethane; Dioxane or 1,4-dioxane represents 1,4 -dioxane; MeCN, ACN or CH3CN represents acetonitrile; MeOH or methanol represents methanol; EtOH or ethanol represents ethanol; DEA represents diethylamine; DIPEA or DIEA represents N,N-diisopropylethylamine; TEA represents triethylamine; DIAD represents diisopropyl azodicarboxylate; Xantphos represents 4,5-bis(diphenylphosphino-9,9-dimethylxanthene); DMAP represents 4-dimethylaminopyridine; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EA or EtOAc represents ethyl acetate; PE represents petroleum ether; THF represents tetrahydrofuran; Toluene or tol.represents toluene; SOCl2 represents dichlorothionyl; TFA represents trifluoroacetic acid; FA represents formic acid; TMSCN represents trimethylsilyl cyanide; H2O represents water; HCl represents hydrogen chloride gas; HCl aq. stands for aqueous hydrochloric acid; °C stands for degrees Celsius; rt or RT stands for room temperature; h stands for hour; min stands for minute; g stands for gram; mg stands for milligram; mL stands for milliliter; mmol stands for millimole; M stands for mole; cm stands for centimeter; mm stands for millimeter; μm stands for micrometer; nm stands for nanometer; mL / min stands for milliliter per minute; Hz stands for hertz; MHz stands for megahertz; bar stands for bar; psi stands for pounds per square inch; N2 stands for nitrogen; HPLC stands for high performance liquid chromatography; ID stands for inner diameter; LCMS or LC-MS stands for liquid chromatography-mass spectrometry; m / z stands for mass-to-charge ratio; ESI stands for electrospray ionization; CO2 stands for carbon dioxide; TLC stands for thin-layer chromatography; Rf stands for the relative migration value of the sample after application / development on the TLC plate; UV stands for ultraviolet; IV stands for intravenous injection; PO stands for oral administration; rpm stands for revolutions per minute; ATCC stands for American Type Culture Collection.

[0115] Example 1: Preparation of Compound 1

[0116] Preparation of compound 1-2

[0117] Compound 1-1 (120.0 g, 643.1 mmol) was dissolved in MeCN (1.2 L) and cooled to 0°C in an ice-water bath. p-Toluenesulfonic acid monohydrate (122.2 g, 643.1 mmol) was added and stirred at this temperature for 30 minutes. NIS (173.6 g, 771.1 mmol) was then added. After the addition, the ice-water bath was removed and the reaction system was stirred at room temperature for 16 hours. Sodium sulfite was added to the reaction system to quench the reaction. Water (3 L) was added and the mixture was extracted with ethyl acetate (2 L x 2). The organic phase was washed with saturated brine (2 L x 3) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by normal phase silica gel chromatography (EA / PE = 0-30%) to afford the title compound 1-2 (168.0 g, white solid, 84% yield).

[0118] Preparation of Compounds 1-3

[0119] Compound 1-2 (163.0 g, 0.52 mol) was dissolved in DMF (800 mL), and cesium carbonate (338.9 g, 1.04 mol), 1-bromo-2-chloroethane (149.1 g, 1.04 mol), and H2O (12 mL) were added sequentially. The temperature was raised to 65°C and the reaction was allowed to proceed for 16 h. After the reaction was completed, the mixture was filtered, and water (3 L) was added to the filtrate. The mixture was extracted with ethyl acetate (2 L × 2), and the organic phase was washed with saturated brine (2 L × 3), dried over anhydrous sodium sulfate, and concentrated. The organic phase was purified by normal phase silica gel chromatography (EA / PE = 0-30%) to obtain the title compound 1-3 (136.9 g, white solid, yield 70%).

[0120] Preparation of Compounds 1-4

[0121] Compound 1-3 (168.0 g, 448.0 mmol) was dissolved in DMF (1 L), and CuCN (100.3 g, 1120.0 mmol) and CuI (73.1 g, 385.4 mmol) were added. The reaction was heated to 140°C and allowed to react for 4 hours. Completion of the reaction was monitored by TLC (PE / EA = 5 / 1, product Rf ≈ 0.5). The mixture was filtered through a thin layer of Celite, and the filter cake was rinsed with ethyl acetate. The filtrate was collected and added to water (4 L). The mixture was extracted with ethyl acetate (3 L x 2). The organic phase was washed with saturated brine (2 L x 3) and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by normal phase silica gel chromatography (EA / PE = 0-20%) to afford the title compound 1-4 (66.7 g, white solid, 54% yield). 1 H NMR (400MHz, CDCl3) δ 8.46 (d, J=5.2Hz, 1H), 6.93 (d, J=5.2Hz, 1H), 5.32 (s, 2H), 2.51 (s, 3H), 2.05 (s, 2H).

[0122] Preparation of Compounds 1-5

[0123] Compound 1-4 (5 g, 18 mmol) was added to a three-necked flask, the atmosphere was replaced with nitrogen three times, anhydrous tetrahydrofuran (20 mL) was added, and methylmagnesium bromide (3.0 M, 18 mL, 54 mmol) was added dropwise at -10°C. The reaction system was stirred at 0°C for 2 hours, and the reaction was completed. Saturated aqueous ammonium chloride solution (50 mL) was slowly added to the reaction system under an ice bath, and extracted with EtOAc (50 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (EtOAc / PE = 0-20%) to obtain the title compound 1-5 (3 g, light yellow liquid, yield 60%). 1H NMR (400MHz, DMSO-d6) δ7.90 (d, J=2.2Hz, 1H), 7.83 (d, J=2.2Hz, 1H), 5.37 (s, 1H), 4.43 (t, J=4.0Hz, 2H), 3.97 (t, J=4.0Hz, 2H), 1.43 (s, 6H).

[0124] Preparation of Compounds 1-6

[0125] Compound 1-5 (3 g, 10.9 mmol) was added to a three-necked flask, followed by anhydrous THF (30 mL) and phenol (3 g, 32.8 mmol). Boron trifluoride etherate (9.71 g, 32.8 mmol) was then added at 0°C. The reaction system was stirred at 0°C for 3 hours. After completion of the reaction, ice water (20 mL) was slowly added to quench the reaction, and the mixture was extracted with EtOAc (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was separated and purified by a normal phase silica gel column (EtOAc / PE = 0-20%) to obtain the title compound 1-6 (2.3 g, light yellow liquid, yield 57%). 1 H NMR (400MHz, DMSO-d6) δ9.29 (s, 1H), 7.61 (d, J = 2.2Hz, 1H), 7.54 (d, J = 2.2Hz, 1H), 7 .04 (d, J=8.6Hz, 2H), 6.69 (d, J=8.6Hz, 2H), 4.41 (t, J=4.0Hz, 2H), 3.95 (t, J=4.0Hz 2H), 1.60(s, 6H).

[0126] Synthesis of compounds 1-7

[0127] To a 250 mL three-necked flask, add compound 1-6 (5 g, 14.28 mmol), DCM (50 mL), and pyridine (2.26 g, 28.55 mmol, 2.30 mL). Stir and dissolve. Cool to 0°C. Add Tf2O (6.04 g, 21.41 mmol, 3.60 mL) dropwise at 5°C and stir for 3 hours. TLC monitoring indicates the reaction is complete. Pour the reaction solution into saturated sodium bicarbonate solution (100 mL) and extract twice with DCM (60 mL). The organic phases are combined, washed with water (100 mL), and evaporated to dryness under reduced pressure to obtain a brown-black liquid. Purify by automatic column chromatography (EA:PE = 0-15%) to obtain the title compound 1-7 (6.15 g). LC-MS (ESI): m / z 482.2 [M+H] + .

[0128] Synthesis of compounds 1-8

[0129] To a 100 mL single-necked flask, add compound 1-7 (1 g, 2.07 mmol), 4-hydroxyphenylboronic acid (400.00 mg, 2.90 mmol), 1,4-dioxane (20 mL), H₂O (10 mL), Pd(dppf)Cl₂ (160.00 mg, 218.67 μmol), and Na₂CO₃ (550.00 mg, 5.19 mmol). The atmosphere was purged with nitrogen three times and stirred at 90°C for 10 hours. LCMS monitoring indicated the reaction was complete. Saturated ammonium chloride (100 mL) and ethyl acetate (80 mL) were added, mixed, and filtered through a pad of Celite to remove insoluble matter. The filtrate was allowed to stand, the layers separated, and the aqueous phase extracted once with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and purified by automatic column chromatography (EA:PE = 0-30%) to obtain 0.61 g of the title compound 1-8. LC-MS (ESI): m / z 424.0 [MH] - . 1 H NMR (400MHz, CDCl3) δ7.50-7.44 (m, 5H), 7.38 (d, J=2.4Hz, 1H), 7.21 (d, J=8.4Hz, 2H), 6.90 ( d, J=8.6Hz, 2H), 4.90 (br.s, 1H), 4.43 (t, J=6.2Hz, 2H), 3.88 (t, J=6.2Hz, 2H), 1.69 (s, 6H).

[0130] Synthesis of Compounds 1-9

[0131] To a 50 mL single-necked flask, add compound 1-8 (0.61 g, 1.43 mmol), 2-methylthiopyrimidin-4-ylmethanol (265 mg, 1.70 mmol), TMAD (495 mg, 2.87 mmol), and DCM (10 mL). Cool to 25°C, and add Bu3P (607.50 mg, 3.00 mmol) dropwise. After the addition is complete, slowly warm to room temperature (25°C) and stir for 16 hours. LCMS shows the presence of the desired product molecular ion peak. Evaporate to dryness under reduced pressure and purify using an automated column chromatography (EA / PE = 0-20%) to obtain 0.61 g of the title compound 1-9. LC-MS (ESI): m / z 564.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.54 (d, J=4.8Hz, 1H), 7.54-7.46 (m, 5H), 7.37 (d, J=2.4Hz, 1H), 7.24-7.20 (m, 3H), 7 .02 (d, J=8.8Hz, 2H), 5.14 (s, 2H), 4.43 (t, J=6.4Hz, 2H), 3.88 (t, J=6.4Hz, 2H), 2.60 (s, 3H), 1.69 (s, 6H).

[0132] Synthesis of compound 1

[0133] To a 100 mL single-necked flask, add compound 1-9 (0.61 g, 1.08 mmol) and DCM (10 mL). Cool to 0°C, add m-CPBA (465 mg, 2.29 mmol, 85% purity), slowly warm to room temperature (25°C), and stir for 16 hours. TLC indicated completion of the reaction, and LCMS showed the presence of the desired product molecular ion peak. Add saturated sodium bicarbonate solution (50 mL), and extract twice with DCM (50 mL). The organic phases were combined, washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to dryness under reduced pressure. The resulting residue was purified using an automated column chromatography system (EA / PE = 0-50%) to yield 0.49 g of the title compound 1. LC-MS (ESI): m / z 596.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.93 (d, J=5.2Hz, 1H), 7.85 (d, J=5.2Hz, 1H), 7.55 (d, J=8.8Hz, 2H), 7.50 (d, J=4.2Hz, 1H), 7.48 (d, J=1.9Hz, 2H), 7.37 (d, J=2.4Hz, 1H), 7.23 (d, J=8.4Hz, 2H), 7.03 (d, J=8.8Hz, 2H), 5.34 (s, 2H), 4.43 (t, J=6.2Hz, 2H), 3.88 (t, J=6.2Hz, 2H), 3.39 (s, 3H), 1.70 (s, 6H).

[0134] Example 2: Preparation of Compound 2

[0135] Synthesis of compound 2

[0136] Compound 1 (150 mg, 251.46 μmol), dimethylphosphine oxide (412.50 mg, 5.29 mmol), CH3CN (4 mL), and K2CO3 (75.00 mg, 542.65 μmol) were added to a microwave tube and stirred at 100°C for 3 hours. TLC monitoring indicated complete reaction. Water (30 mL) was added and the mixture was extracted twice with ethyl acetate (40 mL). The organic phases were combined, washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to dryness under reduced pressure. Purification was performed by column chromatography to yield 220 mg of a viscous product. The product was purified by HPLC (Preparative Method: Column: Pntulips ZZ-C18 10 μm, 250 x 20 mm; Column temperature: 25°C; Mobile phase: Water (0.1% FA)-Acetonitrile; Gradient elution: 50%-70% Acetonitrile over 12 minutes; Flow rate: 30 mL / min) and lyophilized to afford 53.77 mg of the title compound 2. LC-MS (ESI): m / z 594.4 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.89 (s, 1H), 7.70 (s, 1H), 7.54 (d, J = 8.4Hz, 2H), 7.49 (d, J = 8.4Hz, 2H), 7.49 (d, J = 2.3Hz, 1H), 7.37 (d, J = 2.3Hz, 1H), 7. 31p NMR (162MHz, DMSO-d6) δ35.11 (s, 1P).

[0137] Example 3: Preparation of Compound 3

[0138] Synthesis of compound 3

[0139] Compound 1 (150 mg, 251.46 μmol), methanesulfonamide (120 mg, 1.26 mmol), CH3CN (3 mL), and K2CO3 (174 mg, 1.26 mmol) were added to a microwave tube and stirred at 100°C for 2 hours. TLC indicated the reaction was complete. The reaction solution was poured into water, ethyl acetate (20 mL) was added, and the pH was adjusted to 6-7. The mixture was filtered and the filter cake was washed with water. Methanol (6 mL) and ethyl acetate (4 mL) were added to the resulting filter cake and the temperature was refluxed for 1 hour. The mixture was cooled to room temperature and stirred for 16 hours. The mixture was filtered and evaporated to dryness under reduced pressure to obtain 89.28 mg of the title compound 3. LC-MS (ESI): m / z 611.4 [M+H] + .1 H NMR (400MHz, DMSO-d6) δ11.37 (br.s, 1H), 8.63 (d, J=5.1Hz, 1H), 7.69 (d, J=2 .3Hz, 1H), 7.63 (d, J=2.4Hz, 1H), 7.61 (d, J=8.8Hz, 2H), 7.56 (d, J=8.4Hz, 2H) , 7.30 (d, J=8.5Hz, 2H), 7.23 (d, J=5.1Hz, 1H), 7.10 (d, J=8.8Hz, 2H), 5.19 (s , 2H), 4.42 (t, J=4.8Hz, 2H), 3.96 (t, J=4.8Hz, 2H), 3.37 (s, 3H), 3.31 (s, 6H).

[0140] Example 4: Preparation of Compound 4

[0141] Preparation of compound 4-1

[0142] Compound 1-7 (1 g, 2.07 mmol) was dissolved in 1,4-dioxane (20.0 mL), and 3-hydroxyphenylboronic acid (400 mg, 2.9 mmol), potassium carbonate (860 mg, 6.2 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (228 mg, 0.31 mmol), and water (2.0 mL) were added. The atmosphere was purged with nitrogen three times, and the reaction system was stirred at 100°C for 5 hours. After completion of the reaction, water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 0-10%) to obtain 700 mg of the title compound 4-1. LC-MS (ESI): m / z 426.2 [M+H] + .

[0143] Preparation of compound 4-2

[0144] Compound 4-1 (450 mg, 1.06 mmol) was dissolved in dichloromethane (10.0 mL), and 2-methylthiopyrimidin-4-ylmethanol (181 mg, 1.16 mmol) and N,N,N,N-tetramethylazodicarbonamide (365 mg, 2.1 mmol) were added sequentially. The atmosphere was purged with nitrogen three times. Tributylphosphine (427 mg, 2.1 mmol) was added under a nitrogen atmosphere, and the reaction system was stirred at room temperature for 1 hour. After the reaction, water (20 mL) was added and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (EA:PE = 0-10%) to obtain 450 mg of the title compound 4-2. LC-MS (ESI): m / z 564.2 [M+H] + .

[0145] Preparation of compound 4

[0146] Compound 4-2 (150 mg, 0.42 mmol) was dissolved in THF (2.0 mL), and a solution of Oxone (576 mg, 1.6 mmol) in H₂O (2.0 mL) was added. The reaction system was stirred at room temperature for 16 hours. After completion of the reaction, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative separation and purification (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 25 mg of the title compound 4. LC-MS (ESI): m / z 596.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.93 (d, J=5.1Hz, 1H), 7.86 (d, J=5.1Hz, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.49 (d, J=2.4Hz, 1H), 7.40 (t, J=8.0Hz, 1H), 7.37 (d, J=2.4Hz, 1H), 7.28- 7.24 (m, 3H), 7.20 (t, J=2.6Hz, 1H), 6.94 (ddd, J=8.2, 2.6, 0.9Hz, 1H), 5.36 (d, J=0 .8Hz, 2H), 4.43 (t, J=6.2Hz, 2H), 3.88 (t, J=6.2Hz, 2H), 3.39 (s, 3H), 1.71 (s, 6H).

[0147] Example 5: Preparation of Compound 5

[0148] Preparation of compound 5

[0149] Compound 4 (50 mg, 0.08 mmol) was dissolved in THF (2.0 mL), and methanesulfonamide (95 mg, 0.12 mmol) and potassium carbonate (30 mg, 0.21 mmol) were added sequentially. The reaction system was stirred at 80°C for 4 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 30 mg of the title compound 5. LC-MS (ESI): m / z 611.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.38 (br.s, 1H), 8.64 (d, J=5.1Hz, 1H), 7.71 (d, J=2.3Hz , 1H), 7.65 (d, J=2.3Hz, 1H), 7.62 (d, J=8.3Hz, 2H), 7.39 (t, J=7.9Hz, 1H), 7.34 (d, J=8.3Hz, 2H), 7.31 (s, 1H), 7.27 (t, J=6.6Hz, 2H), 7.03 (dd, J=8.3, 2.5Hz, 1H), 5. 24(s, 2H), 4.44(t, J=5.2Hz, 2H), 3.97(t, J=5.2Hz, 2H), 3.37(s, 3H), 1.70(s, 6H).

[0150] Example 6: Preparation of Compound 6

[0151] Preparation of compound 6

[0152] Compound 4 (50 mg, 0.08 mmol) was dissolved in tetrahydrofuran (2.0 mL), and dimethylphosphine oxide (20 mg, 0.025 mmol) was added. The reaction system was stirred at 80°C for 5 hours. After the reaction, water (20 mL) was added and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 22 mg of the title compound 6. LC-MS (ESI): m / z 594.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.93 (d, J=5.1Hz, 1H), 7.69 (dd, J=5.2, 3.2Hz, 1H), 7.63 (d, J=2.3Hz, 1H), 7.59-7.55 (m, 2H), 7.54 (s, 1H), 7.32 (t, J=7.9Hz, 1H), 7.28 (s, 1H), 7 .25(d, J=8.3Hz, 2H), 7.23-7.18(m, 1H), 6.98(dd, J=8.2, 2.5Hz, 1H), 5.32(s, 2H), 4 .36(t, J=5.2Hz, 2H), 3.89(t, J=5.2Hz, 2H), 1.69(d, J=13.7Hz, 6H), 1.62(s, 6H).31p NMR (162MHz, DMSO-d6) δ33.99 (s, 1P).

[0153] Example 7: Preparation of Compound 7

[0154] Preparation of compound 7-1

[0155] To a 100 mL single-necked flask, compound 1-8 (190 mg, 445.66 μmol), DMF (4 mL), 2-chloro-4-(chloromethyl)pyrimidine (119.85 mg, 735.26 μmol, 85 μL), and K2CO3 (125 mg, 904.45 μmol) were added. The mixture was stirred at room temperature for 5 hours. TLC indicated that the reaction was essentially complete. Water (50 mL) was added and the mixture was extracted twice with ethyl acetate (40 mL). The organic phases were combined, washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. Purification was performed on an automated column chromatography system (EA:PE = 10-100%) to obtain 210 mg of the title compound 7-1. LC-MS (ESI): m / z 552.2 [M+H]+ . 1 H NMR (400MHz, CDCl3) δ8.65 (d, J=5.0Hz, 1H), 7.56 (d, J=4.5Hz, 1H), 7.54 (d, J=8.9Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 7.49 (d, J=2.4Hz, 1H), 7.37 (d .

[0156] Preparation of compound 7

[0157] Compound 7-1 (210 mg, 0.38 mmol) was dissolved in DMF (2.0 mL) and tris(dibenzylideneacetone)dipalladium (70 mg, 0.08 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (44 mg, 0.08 mmol), DIEA (148 mg, 0.8 mmol), and 1-imino-1-oxothiolane (50 mg, 0.42 mmol) were added in sequence. The reaction system was stirred at 100°C for 16 hours. After the reaction, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 37 mg of the title compound 7. LC-MS (ESI): m / z 635.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.47 (d, J=5.1Hz, 1H), 7.69 (d, J=2.3Hz, 1H), 7.63 (d, J=2.3Hz, 1 H), 7.60 (d, J=8.8Hz, 2H), 7.55 (d, J=8.5Hz, 2H), 7.30 (d, J=8.5Hz, 2H), 7.08 (d, J=8.8Hz , 2H), 6.98 (d, J=5.1Hz, 1H), 5.10 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 3.95 (t, J=5.2Hz, 2H), 3 .62-3.52(m, 2H), 3.40-3.31(m, 2H), 2.27-2.16(m, 2H), 2.15-2.05(m, 2H), 1.68(s, 6H).

[0158] Example 8: Preparation of Compound 8

[0159] Preparation of compound 8-1

[0160] Compound 4-1 (105 mg, 0.25 mmol) was dissolved in acetonitrile (2.0 mL), and 2-chloro-4-(chloromethyl)pyrimidine (40 mg, 0.25 mmol) and potassium carbonate (102 mg, 0.75 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the reaction system was stirred at 100°C for 5 hours. After the reaction, water (10 mL) was added, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (EA:PE = 0-30%) to obtain 127 mg of the title compound 8-1. LC-MS (ESI): m / z 552.0 [M+H] + .

[0161] Preparation of compound 8

[0162] Compound 8-1 (127 mg, 0.23 mmol) was dissolved in DMF (2.0 mL) and tris(dibenzylideneacetone)dipalladium (42 mg, 0.05 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (27 mg, 0.05), DIEA (88 mg, 0.7 mmol), and 1-imino-1-oxothiolane (30 mg, 0.25 mmol) were added in sequence. The reaction system was stirred at 100°C for 16 hours. After the reaction, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 2 mg of the title compound 8. LC-MS (ESI): m / z 635.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.47 (d, J=5.1Hz, 1H), 7.71 (d, J=2.4Hz, 1H), 7.65 (d, J=2.3Hz , 1H), 7.60 (d, J=8.5Hz, 2H), 7.37 (t, J=7.9Hz, 1H), 7.33 (d, J=8.5Hz, 2H), 7.28-7.23 (m , 2H), 7.02-6.97 (m, 2H), 5.14 (s, 2H), 4.43 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 3. 62-3.51(m, 2H), 3.40-3.32(m, 2H), 2.25-2.14(m, 2H), 2.14-2.04(m, 2H), 1.70(s, 6H).

[0163] Example 9: Preparation of Compound 9

[0164] Preparation of compound 9-2

[0165] Under nitrogen, compound 9-1 (500 mg, 3.11 mmol), 2-methylthio-4-chloropyrimidine (626.50 mg, 3.11 mmol), and THF (10 mL) were added to a reaction flask. NaH (149.40 mg, 3.74 mmol, 60% purity) was added portionwise at 0°C. The mixture was slowly warmed to room temperature and stirred for 16 hours. LCMS confirmed the reaction was complete. Water (10 mL) was added, and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was separated and purified on a normal phase silica gel column (EtOAc / PE = 0-10%) to obtain 1.0 g of the title compound 9-2. LC-MS (ESI): 326.2 [M+H] + .

[0166] Preparation of compound 9-3

[0167] Under nitrogen, compound 9-2 (1 g, 3.07 mmol) and DCM (10 mL) were added to a reaction flask. A dioxane hydrochloride solution (4.0 M, 30.73 mmol, 7.68 mL) was added dropwise at 0°C and stirred at room temperature for 3 hours. After the reaction, the supernatant was decanted and the residue was dissolved in water (20 mL). The pH was then adjusted to alkaline with cesium carbonate. The mixture was extracted with DCM (10 mL) three times, dried over anhydrous sodium sulfate, filtered, and dried to give 530 mg of the title compound 9-3. LC-MS (ESI): 226.2 [M+H] + .

[0168] Preparation of compound 9-4

[0169] Under nitrogen protection, compound 9-3 (112.12 mg, 497.62 μmol), compound 1-7 (200 mg, 414.68 μmol), cesium carbonate (405.33 mg, 1.24 mmol), Pd(OAc)2 (9.31 mg, 41.47 μmol), BINAP (51.64 mg, 82.94 μmol) and dioxane (5 mL) were added to a microwave tube and stirred at 110°C for 2 hours. Filtered, the filtrate was dried. The crude product was purified by column chromatography with EA / PE = 0-100% to obtain 180 mg of the title compound 9-4. LC-MS (ESI): 557.2 [M+H] + .

[0170] Preparation of compound 9-5

[0171] Compound 9-4 (30 mg, 53.81 μmol) and DCM (1 mL) were added to a reaction flask at 0°C, followed by m-CPBA (27.86 mg, 161.43 μmol). The temperature was slowly raised to room temperature and stirred for 2 hours. Saturated aqueous sodium carbonate solution (10 mL) was added, and the mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated and purified on a normal phase silica gel column (EtOAc / PE = 0-100%) to obtain 10 mg of the title compound 9-5. LC-MS (ESI): 605.2 [M+H] + .

[0172] Preparation of compound 9

[0173] Compound 9-5 (10 mg, 16.51 μmol), dimethylphosphine oxide (3.87 mg, 49.54 μmol), Cs2CO3 (16.14 mg, 49.54 μmol), and acetonitrile (2 mL) were added to a reaction flask and stirred at 80°C for 2 hours. Filter and spin dry to obtain 10 mg of the crude title compound 9. LC-MS (ESI): 603.2 [M+H] + .

[0174] Example 10: Preparation of Compound 10

[0175] Preparation of compound 10

[0176] Under nitrogen, compound 9 (50 mg, 82.85 μmol), CuI (31.56 mg, 165.71 μmol), DIEA (21.42 mg, 165.71 μmol, 28.86 μL), and THF (1 mL) were added to a reaction flask and stirred at room temperature for 2 hours. The mixture was filtered and dried. 2 mL of water was added, and the mixture was extracted three times with dichloromethane (2 mL). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-80% acetonitrile over 30 minutes; flow rate: 30 mL / min) to obtain 13 mg of the title compound 10. LC-MS (ESI): 587.2 [M+H] + . 1HNMR (400MHz, DMSO-d6) δ8.66 (dd, J=5.9, 1.0Hz, 1H), 7.62 (d, J=2.3Hz, 1H), 7.56 (d, J= 2.3Hz, 1H), 7.09 (d, J=8.6Hz, 2H), 7.04 (dd, J=5.9, 2.7Hz, 1H), 6.92 (d, J=8.6Hz, 2H), 5. 36-5.24 (m, 1H), 4.41 (t, J=5.2Hz, 2H), 3.95 (t, J=5.2Hz, 2H), 3.55-3.45 (m, 2H), 3.13- 3.03 (m, 2H), 2.17-2.08 (m, 2H), 1.87-1.77 (m, 2H), 1.74 (d, J=13.7Hz, 6H), 1.62 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.05 (s, 1P).

[0177] Example 11: Preparation of Compound 11

[0178] Preparation of compound 11-1

[0179] Compound 1-7 (1 g, 1.87 mmol) and (N-tert-butyloxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (309 mg, 1.87 mmol) were dissolved in 1,4-dioxane (10.0 mL). Cesium carbonate (1.22 g, 3.73 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (272.93 mg, 373.00 μmol) were added sequentially. The atmosphere was purged with nitrogen three times and stirred at 105°C for 5 hours. After completion of the reaction, the mixture was cooled to room temperature and the insoluble matter was filtered off. Saturated aqueous sodium chloride solution (10 mL) was added to the filtrate, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried, and concentrated to obtain a crude product, which was separated and purified by a normal phase silica gel column (EtOAc / PE = 0-40%) to obtain 820 mg of the title compound 11-1, with a yield of 77.22%. LC-MS (ESI): 459.2 [M+Ht-Bu] + .

[0180] Preparation of compound 11-2

[0181] Compound 11-1 (1.0 g, 1.94 mmol) was dissolved in dichloromethane (10 mL). The reaction system was cooled to 0°C and trifluoroacetic acid (3 mL) was added dropwise. The reaction was stirred for 3 hours. Upon completion, the reaction solution was concentrated to obtain the crude product 11-2 (0.8 g), which was used directly in the next reaction. LC-MS (ESI): m / z 415.0 [M+H] + .

[0182] Preparation of compound 11-3

[0183] Compound 11-2 (450 mg, 1.08 mmol) and potassium carbonate (150 mg, 1.08 mmol) were added to a single-necked flask. Anhydrous acetonitrile (5 mL) was added to the single-necked flask, cooled to 0°C, and a solution of 2-chloro-4-(chloromethyl)pyrimidine (177 mg, 1.08 mmol) in acetonitrile (1 mL) was slowly added dropwise. The reaction system was stirred at 0°C for 60 minutes, then quenched by adding saturated sodium bicarbonate solution (20 mL). The reaction system was extracted three times with EtOAc (15 mL). The organic phases were combined, dried, and concentrated to obtain the crude product, which was separated and purified by normal phase silica gel column chromatography (EtOAc / PE = 0-30%) to obtain 200 mg of the title compound 11-3 in a yield of 34%. LC-MS (ESI): m / z 541.2 [M+H] + .

[0184] Preparation of compound 11

[0185] Compound 11-3 (40 mg, 0.074 mmol), DIEA (28 mg, 0.029 mmol), 1-aminotetrahydrothiophene-1-oxide (26 mg, 0.224 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 0.007 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (8 mg, 0.014 mmol) were dissolved in 1,4-dioxane. The reaction system was purged with nitrogen three times and stirred in a microwave at 100°C for 2 hours. After completion of the reaction, the reaction system was filtered and the filtrate was concentrated to obtain the crude product, which was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain the title compound 11 (8 mg). LC-MS (ESI): m / z 624.3 [M+H] + . 1H NMR (400MHz, Chloroform-d) δ8.50 (d, J=4.8Hz, 1H), 7.42 (d, J=2.4Hz, 1H), 7.34-7.3 0 (m, 4H), 7.14 (d, J = 8.4Hz, 2H), 6.03 (s, 1H), 4.42 (t, J = 6.2Hz, 2H), 4.01-3.94 (m, 2H) , 3.87 (t, J=6.2Hz, 2H), 3.75-3.68 (m, 2H), 3.64-3.56 (m, 2H), 3.46-3.39 (m, 2H), 3.2 1-3.06 (m, 2H), 2.84-2.74 (m, 2H), 2.41-2.31 (m, 2H), 2.31-2.21 (m, 2H), 1.66 (s, 6H).

[0186] Example 12: Preparation of Compound 12

[0187] Preparation of compounds 12-1 and 12-2

[0188] At room temperature, 2-chloro-4-bromopyrimidine (619.15 mg, 3.20 mmol), (2-(methylthio)pyrimidin-4-yl)methanol (500 mg, 3.20 mmol), Cs2CO3 (2.09 g, 6.40 mmol), and acetonitrile (5 mL) were added to a reaction flask and stirred at 80°C for 16 hours. The mixture was filtered and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified on a normal phase silica gel column (EtOAc / PE = 0-20%) to obtain the title compound 12-1 (200 mg, 20% yield) and compound 12-2 (500 mg, 58% yield). Compound 12-1, LC-MS (ESI): m / z 313.0 [M+H] + Compound 12-2, LC-MS (ESI): m / z 269.0 [M+H] + .

[0189] Preparation of compound 12-3

[0190] Compound 1-7 (11.0 g, 22.81 mmol) and pinacol diboron (5.79 g, 22.81 mmol) were dissolved in 1,4-dioxane (110.0 mL). 1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (0.83 g, 1.14 mmol) and a potassium carbonate aqueous solution (2 mol / L, 28.50 mL, 57.02 mmol) were added. The atmosphere was replaced with argon four times and heated to 110°C with stirring for 16 hours. After completion of the reaction, the reaction system was cooled to room temperature, the insoluble solids were filtered out through a pad of celite, and the filter cake was rinsed with ethyl acetate. The filtrates were combined, water (150 mL) was added, and the mixture was extracted twice with ethyl acetate (300 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (ethyl acetate / petroleum ether = 0-10%) to obtain 10.0 g of the title compound 12-3 in an 86.9% yield. LC-MS (ESI): m / z 477.2 [M+H2O] + .

[0191] Preparation of compound 12-4

[0192] Under nitrogen, compound 12-3 (400 mg, 869.19 μmol), compound 12-1 (544.41 mg, 1.74 mmol), K2CO3 (360.38 mg, 2.61 mmol), Pd(dppf)Cl2 (63.60 mg, 86.92 μmol), H2O (1 mL), and 1,4-dioxane (5 mL) were added to a reaction flask and stirred at 80°C for 2 hours. The mixture was spin-dried and the crude product was purified by normal phase silica gel column chromatography (PE / EtOAc = 0-50%) to obtain 320 mg of the title compound 12-4 in a 64% yield. LC-MS (ESI): 566.2 [M+H] + .

[0193] Preparation of compound 12-5

[0194] Compound 12-4 (100 mg, 176.52 μmol) was dissolved in DCM (1 mL). m-CPBA (67.02 mg, 388.35 μmol) was added to the reaction flask at 0°C, and the temperature was slowly raised to room temperature with stirring for 2 hours. DCM (5 mL) was added to the system, and the mixture was washed three times with saturated aqueous sodium carbonate (5 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain 100 mg of the title compound 12-5 in a 94% yield. LC-MS (ESI): 598.2 [M+H] + .

[0195] Preparation of compound 12

[0196] 2-Thia-6-azaspiro[3.3]heptane-2,2-dioxide hydrochloride (46.03 mg, 250.63 μmol), compound 12-5 (100 mg, 167.08 μmol), DIEA (215.95 mg, 1.67 mmol, 291.03 μL), and acetonitrile (1 mL) were added to a reaction flask and stirred at 80°C for 2 hours. The crude product was obtained by spin drying. The crude product was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-60% acetonitrile over 30 minutes; flow rate: 30 mL / min) to obtain 30 mg of the title compound 12. LC-MS (ESI): 665.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.66 (d, J=5.2Hz, 1H), 8.35 (d, J=5.2Hz, 1H), 8.10-8.08 (m, 2H), 7.72 (d, J=5.2Hz, 1H), 7.69 (d, J=2.4Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.42-7.40 (m, 2H), 6.74 (d, J=4.8Hz, 1H), 5.37 (s, 2H), 4.49 (s, 4H ), 4.42 (t, J=5.2Hz, 2H), 4.26 (s, 4H), 3.95 (t, J=5.2Hz, 2H), 1.70 (s, 6H).

[0197] Example 13: Preparation of Compound 13

[0198] Preparation of compound 13-1

[0199] Under nitrogen, compound 12-3 (400 mg, 869.19 μmol), compound 12-2 (350.36 mg, 1.30 mmol), K2CO3 (360.38 mg, 2.61 mmol), Pd(dppf)Cl2 (63.60 mg, 86.92 μmol), 1,4-dioxane (5 mL), and H2O (1 mL) were added to a reaction flask and reacted at 100°C for 16 hours. Water (10 mL) was added and the mixture was extracted with DCM (10 mL) three times. The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was separated and purified on a normal phase silica gel column (EtOAc / PE = 0-100%) to obtain 400 mg of the title compound 13-1 in an 81% yield. LC-MS (ESI): 566.1 [M+H] + .

[0200] Preparation of compound 13-2

[0201] Compound 13-1 (100 mg, 176.52 μmol) and DCM (1 mL) were added to a reaction flask. m-CPBA (67.02 mg, 388.35 μmol) was added at 0°C, and the temperature was slowly raised to room temperature and stirred for 2 hours. DCM (5 mL) was added, and the mixture was washed three times with saturated aqueous sodium carbonate (5 mL), dried over anhydrous sodium sulfate, and spin-dried to obtain 100 mg of the title compound 13-2 in a 94% yield. LC-MS (ESI): 598.2 [M+H] + .

[0202] Preparation of compound 13

[0203] 2-Thia-6-azaspiro[3.3]heptane-2,2-dioxide hydrochloride (46.03 mg, 250.63 μmol), compound 13-2 (100 mg, 167.08 μmol), DIEA (215.95 mg, 1.67 mmol, 291.03 μL), and acetonitrile (1 mL) were added to a reaction flask and stirred at 80°C for 2 hours. The crude product was spin-dried to obtain the target compound, which was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-60% acetonitrile over 30 minutes; flow rate: 30 mL / min) to obtain 30 mg of the title compound 13. LC-MS (ESI): 665.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.66 (d, J=5.6Hz, 1H), 8.36 (d, J=5.2Hz, 1H), 8.24-8.21 (m, 2H), 7.67 (d, J=2.4Hz, 1H), 7.61 (d, J=2.4Hz, 1H), 7.39-7.36 (m, 2H), 7.01 (d, J=5.6Hz, 1H), 6.79 (d, J=5.2Hz, 1H), 5.44 (s, 2H), 4.49 (s, 4H ), 4.42 (t, J=5.2Hz, 2H), 4.25 (s, 4H), 3.95 (t, J=5.2Hz, 2H), 1.69 (s, 6H).

[0204] Example 14:- Preparation of Compound 14

[0205] Preparation of compound 14-1

[0206] Compound 11-2 (0.4 g, 0.963 mmol) and anhydrous methanol (5 mL) were added to a single-necked flask, followed by the addition of Pd / C (0.17 g). The reaction system was replaced with hydrogen three times and allowed to react under 1 atmosphere of hydrogen for 12 hours. Upon completion, the mixture was filtered through a pad of Celite and the filtrate was concentrated to yield 400 mg of the crude title compound 14-1, which was used directly in the next reaction. LC-MS (ESI): m / z 417.2 [M+H] + .

[0207] Preparation of compound 14-2

[0208] Compound 14-1 (0.400 g, 0.958 mmol), DIEA (371 mg, 2.88 mmol), and anhydrous acetonitrile (5 mL) were added to a single-necked flask and cooled to 0°C. A solution of 2-chloro-4-(chloromethyl)pyrimidine (163 mg, 0.958 mmol) in acetonitrile (1 mL) was slowly added dropwise at 0°C. The mixture was stirred at 0°C for 60 minutes. Saturated sodium bicarbonate solution (10 mL) was added to the reaction system to quench the reaction. The mixture was extracted three times with EtOAc (15 mL). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was separated and purified by normal phase silica gel column chromatography (EtOAc / PE = 0-30%) to obtain the title compound 14-3 (280 mg) in a 53% yield. LC-MS (ESI): m / z 543.2 [M+H] + .

[0209] Preparation of compound 14

[0210] Compound 14-2 (280 mg, 0.517 mmol), DIEA (200 mg, 1.55 mmol), 1-aminodihydrothiophene-1-oxide (119 mg, 0.184 mmol), tris(dibenzylideneacetone)dipalladium (47 mg, 0.051 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (60 mg, 0.1034 mmol), and 1,4-dioxane (5 mL) were added to a reaction flask. The reaction system was replaced with nitrogen three times and microwaved at 100° C. for 2 hours. After the reaction, the mixture was cooled to room temperature. The reaction system was filtered, water (15 mL) was added, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, dried, and concentrated to obtain a crude product, which was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 100 mg of the title compound 14. LC-MS (ESI): m / z 626.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.41 (d, J=5.1Hz, 1H), 7.66 (d, J=2.3Hz, 1H), 7.60 (d, J=2.3Hz, 1H), 7.22-7.15 (m, 4H), 6.97 (d, J=5.1Hz, 1H), 4.41 (t, J=5.4Hz , 2H), 3.95 (t, J=5.4Hz, 2H), 3.52-3.61 (m, 4H), 3.31-3.38 (m, 6H), 2.95-2. 98(m, 2H), 2.46(m, 1H), 2.17-2.26(m, 4H), 2.08-2.14(m, 2H), 1.64(s, 6H).

[0211] Example 15: Preparation of Compound 15

[0212] Preparation of compound 15-1

[0213] 2-Bromo-5-hydroxypyridine (300 mg, 1.72 mmol), 2-chloro-4-(chloromethyl)pyrimidine (421.57 mg, 2.59 mmol), KCO (476.58 mg, 3.45 mmol), and acetonitrile (3 mL) were added to a reaction flask, stirred at 70°C for 16 hours, filtered, and the filtrate concentrated to obtain a crude product. The crude product was separated and purified on a normal phase silica gel column (EtOAc / PE = 0-20%) to obtain 300 mg of the title compound 15-1 in a 57% yield. LC-MS (ESI): 300.0 [M+H] + .

[0214] Preparation of compound 15-2

[0215] Under nitrogen, compound 12-3 (100 mg, 217.30 μmol), compound 15-1 (97.96 mg, 325.95 μmol), K2CO3 (90.09 mg, 651.89 μmol), Pd(dppf)Cl2 (31.80 mg, 43.46 μmol), 1,4-dioxane (1 mL), and H2O (0.2 mL) were added to a reaction flask and stirred at 70°C for 3 hours. The mixture was dried and the crude product was purified by normal phase silica gel column chromatography (EtOAc / PE = 0-50%) to obtain 50 mg of the title compound 15-2 in a 41% yield. LC-MS (ESI): 553.2 [M+H] + .

[0216] Preparation of compound 15

[0217] Dimethylphosphine oxide (21.14 mg, 270.82 μmol) and compound 15-2 (100 mg, 180.55 μmol) were dissolved in DMF (1 mL), and then Pd2(dba)3 (16.52 mg, 18.05 μmol), Xantphos (20.89 mg, 36.11 μmol), and DIEA (116.67 mg, 902.75 μmol, 157.24 μL) were added. The atmosphere was replaced with nitrogen three times, and microwave reaction was carried out at 120°C for 2 hours. The crude product was filtered and dried to give the title compound. The crude product was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; chromatographic column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 10%-80% acetonitrile over 30 minutes; flow rate: 30 mL / min) to give 30 mg of the title compound 15. LC-MS (ESI): 595.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.02 (d, J=5.2Hz, 1H), 8.50 (d, J=3.2Hz, 1H), 7.97-7.95 ( m, 2H), 7.92 (d, J=8.8Hz, 1H), 7.78 (dd, J=5.2, 3.2Hz, 1H), 7.69 (d, J=2.4Hz, 1H), 7 .62 (d, J=2.4Hz, 1H), 7.60 (dd, J=8.8, 3.2Hz, 1H), 7.35-7.33 (m, 2H), 5.44 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 3.95 (t, J=5.2Hz, 2H), 1.76 (d, J=13.6Hz, 6H), 1.69 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.16 (s, 1P).

[0218] Example 16: Preparation of Compound 16

[0219] Preparation of compound 16

[0220] Compound 15-2 (100 mg, 180.55 μmol), 1-aminotetrahydrothiophene-1-oxide (32.28 mg, 270.82 μmol), cesium carbonate (117.65 mg, 361.10 μmol), Xantphos (20.89 mg, 36.11 μmol), Pd2(dba)3 (16.53 mg, 18.05 μmol), and dioxane (1 mL) were added to a microwave tube and stirred at 100°C for 2 hours under nitrogen protection. Filtration and spin-drying gave a crude product, which was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 10%-80% acetonitrile over 30 minutes; flow rate: 30 mL / min) to yield 20 mg of the title compound 16. LC-MS (ESI): 636.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.49 (d, J=5.2Hz, 1H), 8.44 (d, J=2.8Hz, 1H), 7.95-7.93 (m, 2H), 7.89 (d, J=8.8Hz, 1H), 7.69 (d, J=2.4Hz, 1H), 7.62 (d, J=2.4Hz, 1H), 7.52 (dd, J=8.8, 2.8Hz, 1H), 7. 34-7.32 (m, 2H), 7.02 (d, J=5.2Hz, 1H), 5.19 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 3.95 (t, J=5.2Hz, 2H), 3.61-3.54(m, 2H), 3.26-3.21(m, 2H), 2.24-2.17(m, 2H), 2.14-2.07(m, 2H), 1.68(s, 6H).

[0221] Example 17: Preparation of Compound 17

[0222] Preparation of compounds 17-1 and 17-2

[0223] The compound 2-hydroxy-5-iodopyridine (0.990 g, 4.48 mmol), potassium carbonate (1.236 g, 8.96 mmol), and 2-chloro-4-(chloromethyl)pyrimidine (0.730 g, 4.48 mmol) were dissolved in DMF (10 mL). The reaction system was heated to 80° C. and stirred for 3 hours. After completion, the mixture was diluted with ethyl acetate (50 mL) and washed three times with a 5% aqueous lithium chloride solution. The organic phase was separated, dried, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc / PE = 0-100%) to obtain 210 mg of the title compound 17-1 (yield 13.5%) and 800 mg of the title compound 17-2 (yield 51%). Compound 17-1, LC-MS (ESI): m / z 348.0 [M+H] + Compound 17-2, LC-MS (ESI): m / z 348.0 [M+H] + .

[0224] Preparation of compound 17-3

[0225] Compound 17-1 (0.250 g, 0.543 mmol), compound 12-3 (0.189 g, 0.543 mmol), potassium carbonate (0.187 g, 1.36 mmol), and Pd(dppf)Cl2 (0.039 g, 0.054 mmol) were added to a single-necked flask. 1,4-Dioxane (8 mL) and water (2 mL) were added to the single-necked flask. The reaction system was purged with nitrogen three times and heated to 90°C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to obtain the crude product, which was separated and purified by a normal phase silica gel column (EtOAc / PE = 0-30%) to obtain 250 mg of the title compound 17-3 in an 83% yield. LC-MS (ESI): m / z 553.1 [M+H] + .

[0226] Preparation of compound 17

[0227] Compound 17-3 (70 mg, 0.126 mmol), DIEA (49 mg, 0.379 mmol), phosphorus dimethoxide (30 mg, 0.379 mmol), tris(dibenzylideneacetone)dipalladium (12 mg, 0.012 mmol), and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (7 mg, 0.012 mmol) were dissolved in DMF (5 mL). The reaction system was purged with nitrogen three times and stirred in a microwave at 130°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and water (10 mL) was added. The reaction system was filtered and extracted three times with dichloromethane (20 mL). The mixture was washed three times with a 5% aqueous lithium chloride solution, and the organic phase was separated. The organic phases were combined, dried, filtered, and concentrated to give the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to give 30 mg of the title compound 17. LC-MS (ESI): m / z 595.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.84 (d, J=5.2Hz, 1H), 8.34 (d, J=2.4Hz, 1H), 7.89 (dd, J=8.4, 2.4Hz, 1H), 7.56-7.53 (m, 1H), 7.50 (m, 1H), 7.48 (d, J=8.4Hz, 2H), 7. 36 (d, J=2.4Hz, 1H), 7.27 (d, J=8.4Hz, 2H), 7.01 (d, J=8.4Hz, 1H), 5.63 (s, 2H), 4 .44 (t, J=6.2Hz, 2H), 3.89 (t, J=6.2Hz, 2H), 1.90 (d, J=13.5Hz, 6H), 1.71 (s, 6H). 31 PNMR (162MHz, Chloroform-d) δ 35.16.

[0228] Example 18: Preparation of Compound 18

[0229] Preparation of compound 18

[0230] Compound 17-3 (45 mg, 0.081 mmol), DIEA (31 mg, 0.243 mmol), 1-aminotetrahydrothiophene-1-oxide (30 mg, 0.379 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 0.008 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (5 mg, 0.008 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction system was purged with nitrogen three times and stirred in a microwave at 100° C. for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the reaction system was filtered, and the filtrate was concentrated to obtain the crude product, which was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 30 mg of the title compound 18. LC-MS (ESI): m / z 636.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.47 (d, J=5.2Hz, 1H), 8.33 (d, J=2.8Hz, 1H), 7.84 (dd, J=8.4, 2.4Hz , 1H), 7.48 (d, J=2.3Hz, 1H), 7.47 (d, J=8.4Hz, 2H), 7.36 (d, J=2.4Hz, 1H), 7.26 (d, J=8.4Hz, 2H), 7. 01 (d, J=5.2Hz, 1H), 6.96 (dd, J=8.4, 0.8Hz, 1H), 5.46 (s, 2H), 4.43 (t, J=6.2Hz, 2H), 3.88 (t, J=6. 2Hz, 2H), 3.74-3.68(m, 2H), 3.44-3.37(m, 2H), 2.38-2.33(m, 2H), 2.31-2.25(m, 2H), 1.70(s, 6H).

[0231] Example 19: Preparation of Compound 19

[0232] Preparation of compound 19

[0233] Compound 17-3 (75 mg, 0.135 mmol), DIEA (53 mg, 0.406 mmol), 19-1 (27 mg, 0.203 mmol), tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (8 mg, 0.013 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction system was purged with nitrogen three times and stirred in a microwave at 100° C. for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, and concentrated to obtain the crude product, which was then purified by preparative separation (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 10 mg of the title compound 19. LC-MS (ESI): m / z 652.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.43 (d, J=5.2Hz, 1H), 8.33 (d, J=2.5Hz, 1H), 7.84 (dd, J=8.6, 2.5Hz, 1H), 7.48 (d, J=2.3Hz, 1H), 7.46 (d, J=8.4Hz, 2H), 7.36 (d, J=2.3Hz, 1H), 7.25 (d, J=8 .4Hz, 2H), 6.98 (d, J=5.2Hz, 1H), 6.95 (d, J=8.6Hz, 1H), 5.44 (s, 2H), 4.43 (t, J=6.1Hz, 2H), 4.24-4.13 (m, 4H), 3.88 (t, J=6.1Hz, 2H), 3.86-3.81 (m, 2H), 3.52-3.47 (m, 2H), 1.69 (s, 6H).

[0234] Example 20: Preparation of Compound 20

[0235] Preparation of compound 20-1

[0236] Compound 17-2 (0.120 g, 0.347 mmol), compound 12-3 (0.160 g, 0.347 mmol), potassium carbonate (0.144 g, 1.04 mmol), and Pd(dppf)Cl2 (0.025 g, 0.035 mmol) were added to a single-necked flask. 1,4-Dioxane (8 mL) and water (2 mL) were added to the single-necked flask. The reaction system was purged with nitrogen three times and heated to 90°C for 6 hours. After completion of the reaction, the mixture was filtered through Celite pad and the filtrate was concentrated to obtain the crude product. The crude product was separated and purified by a normal phase silica gel column (EtOAc / PE = 0-100%) to obtain 140 mg of the title compound 20-1 in a yield of 72.7%. LC-MS (ESI): m / z 553.1 [M+H] + .

[0237] Preparation of compound 20

[0238] Compound 20-1 (100 mg, 0.180 mmol), DIEA (116 mg, 0.896 mmol), dimethylphosphine oxide (70 mg, 0.896 mmol), tris(dibenzylideneacetone)dipalladium (27 mg, 0.030 mmol), and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (17 mg, 0.030 mmol) were dissolved in DMF (5 mL). The reaction system was purged with nitrogen three times and stirred in a microwave at 130° C. for 2 hours. After the reaction, the reaction system was filtered and the filtrate was concentrated to obtain the crude product, which was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 24 mg of the title compound 20. LC-MS (ESI): m / z 595.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ 8.82 (d, J = 4.4Hz, 1H), 7.71 (m, 2H), 7.46 (d, J = 2.3Hz, 1H), 7.41 (br.s, 1H), 7.37 (d, J = 7.9Hz, 2H), 7.32 (d, J = 2.3Hz, 1H), 7.23 (d, J=7.9Hz, 2H), 6.72 (d, J=9.3Hz, 1H), 5.34 (s, 2H), 4.42 (t, J =6.0Hz, 2H), 3.87 (t, J = 6.0Hz, 2H), 1.84 (d, J = 13.6Hz, 6H), 1.68 (s, 6H). 31P NMR (162MHz, Chloroform-d) δ 35.80.

[0239] Example 21: Preparation of Compound 21

[0240] Preparation of compound 21-2

[0241] Compound 12-3 (448 mg, 1.18 mmol) and (4-bromophenylethynyl)trimethylsilane (330 mg, 1.30 mmol) were dissolved in 1,4-dioxane (5 mL). Potassium carbonate (327 mg, 2.37 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (43.3 mg, 59.2 μmol) were added sequentially. The atmosphere was purged with nitrogen three times and stirred at 105°C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and a saturated aqueous sodium chloride solution (10 mL) was added to the filtrate. The mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried, and concentrated to obtain a crude product. This was separated and purified by a normal phase silica gel column (EtOAc / PE = 0-35%) to obtain 380 mg of the title compound 21-2 in a 63% yield. LC-MS (ESI): 506.2 [M+H] + .

[0242] Preparation of compound 21-3

[0243] Compound 21-2 (300 mg, 592 μmol) and cesium carbonate (385 mg, 1.18 μmol) were added to MeOH (4 mL) and stirred at 25°C for 4 hours. After the reaction, the reaction solution was filtered, and a saturated sodium chloride solution (10 mL) was added to the filtrate. The mixture was extracted three times with dichloromethane (10 mL). The organic phases were combined, dried, concentrated, and separated and purified on a normal phase silica gel column (EtOAc / PE = 0-25%) to obtain 280 mg of the title compound 21-3 in a 65% yield. LC-MS (ESI): 434.1 [M+H] + .

[0244] Preparation of compound 21-4

[0245] Compound 21-3 (250 mg, 575.6 μmol), 2-chloro-4-bromopyrimidine (134 mg, 690.7 μmol), bistriphenylphosphine palladium dichloride (20.2 mg, 28.8 μmol), cuprous iodide (5.5 mg, 28.8 μmol), and N,N-diisopropylethylamine (149 mg, 1.15 mmol) were added to acetonitrile (3 mL) and stirred at 80° C. for 4 hours. After completion of the reaction, saturated aqueous sodium chloride solution (15 mL) was added to the reaction system to quench the reaction. The mixture was extracted three times with ethyl acetate (15 mL). The organic phases were combined, dried, and concentrated to obtain a crude product, which was separated and purified by normal phase silica gel column chromatography (EtOAc / PE = 0-30%) to obtain 150 mg of the title compound 21-4 (yield 47%). LC-MS (ESI): 546.1 [M+H] + .

[0246] Preparation of compound 21

[0247] Compound 21-4 (80 mg, 146.29 μmol) was dissolved in N,N-dimethylformamide (1 mL), and 1-aminotetrahydrothiophene-1-oxide (26.15 mg, 219.43 μmol), N,N-diisopropylethylamine (37.81 mg, 292.57 μmol), tris(dibenzylideneacetone)dipalladium (5.35 mg, 7.31 μmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (4.23 mg, 7.31 μmol) were added in sequence. The atmosphere was purged with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After completion of the reaction, the reaction system was filtered, water (15 mL) was added, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, dried, and concentrated to obtain the crude product, which was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 10% to 45% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 26 mg of the title compound 21. LC-MS (ESI): m / z 629.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.69 (br.s, 2H), 7.75 (d, J=8.5Hz, 2H), 7.72 (d, J=2.3 Hz, 1H), 7.68 (d, J=8.5Hz, 2H), 7.66 (d, J=2.4Hz, 1H), 7.63 (d, J=8.4Hz, 2H), 7 .37(d, J=8.5Hz, 2H), 4.43(t, J=5.1Hz, 2H), 3.97(t, J=5.1Hz, 2H), 3.68-3.61 (m, 2H), 3.46-3.39 (m, 2H), 2.26-2.21 (m, 2H), 2.16-2.08 (m, 2H), 1.70 (s, 6H).

[0248] Example 22: Preparation of Compound 22

[0249] Preparation of compound 22-1

[0250] Compound 1-8 (100 mg, 0.23 mmol) was dissolved in DMF (4 mL) and 2,4-dichloropyrimidine (42 mg, 0.28 mmol) and cesium carbonate (230 mg, 0.7 mmol) were added sequentially. The reaction system was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was added with water (10 mL) and extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed once with saturated brine (3 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 100 mg of the crude product of the title compound 3. LC-MS (ESI): m / z 538.2 [M+H] + .

[0251] Preparation of compound 22

[0252] Compound 22-1 (50 mg, 0.09 mmol) was dissolved in DMF (5.0 mL) and then 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide (21 mg, 0.11 mmol) and cesium carbonate (91 mg, 0.28 mmol) were added. The reaction system was stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was quenched with water (10 mL) and extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed once with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 3.4 mg of the title compound 22. LC-MS (ESI): m / z 649.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.26 (d, J=5.6Hz, 1H), 7.72 (d, J=8.8Hz, 2H), 7.71 (m, 1H), 7.64 (d, J=8.8Hz, 2H), 7.63 (m, 1H), 7.35 (d, J=8.5Hz , 2H), 7.27 (d, J=8.5Hz, 2H), 6.24 (d, J=5.6Hz, 1H), 4.45 (s, 4H), 4.43 (t, J=5.6Hz, 2H), 4.16 (s, 4H), 3.96 (t, J=5.6Hz, 2H), 1.70 (s, 6H).

[0253] Example 23: Preparation of Compound 23

[0254] Preparation of compound 23

[0255] Compound 7-1 (100 mg, 0.19 mmol) was dissolved in acetonitrile (2 mL), and 2-oxa-6-azaspiro[3,3]heptane (31 mg, 0.19 mmol) and DIEA (50 mg, 0.38 mmol) were added sequentially. The reaction system was stirred at 85°C for 12 hours. After completion of the reaction, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative separation and purification (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 12.8 mg of the title compound 23. LC-MS (ESI): m / z 615.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.35 (d, J=4.8Hz, 1H), 7.69 (d, J=2.4Hz, 1H), 7.63 ( d, J=2.4Hz, 1H), 7.59 (d, J=8.8Hz, 2H), 7.55 (d, J=8.2Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.06 (d, J=8.8Hz, 2H), 6.77 (d, J=4.8Hz, 1H), 5.04 (s, 2H), 4.72 (s, 4H), 4.42 (t, J=5.1Hz, 2H), 4.21 (s, 4H), 3.95 (t, J=5.1Hz, 2H), 1.68 (s, 6H).

[0256] Example 24: Preparation of Compound 24

[0257] Preparation of compound 24

[0258] Compound 7-1 (100 mg, 0.19 mmol) was dissolved in acetonitrile (2 mL) and 2-thio-6-azaspiro[3.3]heptane, 2,2-dioxide (28 mg, 0.19 mmol) and DIEA (50 mg, 0.38 mmol) were added in sequence. The reaction system was stirred at 85°C for 12 hours. After the reaction, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 17.6 mg of the title compound 24. LC-MS (ESI): m / z 663.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 8.38 (d, J=5.0Hz, 1H), 7.69 (s, 1H), 7.63 (s, 1H), 7.59 (d, J=8.4Hz, 2H), 7.55 (d, J=8.0Hz, 2H), 7.30 (d, J=8.0Hz, 2H), 7 .07 (d, J=8.4Hz, 2H), 6.82 (d, J=5.0Hz, 1H), 5.06 (s, 2H), 4.51 (s, 4H), 4.42 (t, J=5.2Hz, 2H), 4.28 (s, 4H), 3.95 (t, J=5.2Hz, 2H), 1.68 (s, 6H).

[0259] Example 25: Preparation of Compound 25

[0260] Preparation of compound 25

[0261] Compound 22-1 (60 mg, 0.11 mmol) was dissolved in 1,4-dioxane (6 mL) solution, and then 19-1 (23 mg, 0.16 mmol), Pd2(dba)3 (11 mg, 0.01 mmol), X-phos (13 mg, 0.02 mmol), and DIEA (72 mg, 0.56 mmol) were added. The atmosphere was replaced with nitrogen three times and stirred at 120°C overnight. After the reaction, the reaction mixture was filtered through celite, and the filter cake was rinsed with an appropriate amount of ethyl acetate. The filtrate was added with water (20 mL) and extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 15.0 mg of the title compound 25. LC-MS (ESI): m / z 637.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.34 (d, J=5.6Hz, 1H), 7.73 (d, J=2.4Hz, 1H), 7.72 (d, J=8.4Hz, 2H), 7.67 (d, J=2.3Hz, 1H), 7.63 (d, J=8.4Hz, 2H), 7.36 (d, J=8. 4Hz, 2H), 7.26 (d, J=8.6Hz, 2H), 6.59 (d, J=5.6Hz, 1H), 4.43 (t, J=5.2Hz, 2H ), 3.96 (t, J=5.2Hz, 2H), 3.83-3.89 (m, 4H), 3.58-3.64 (m, 4H), 1.70 (s, 6H).

[0262] Example 26: Preparation of Compound 26

[0263] Preparation of compound 26

[0264] Compound 22-1 (110 mg, 0.20 mmol) was dissolved in 1,4-dioxane (6 mL), and dimethylphosphine oxide (26 mg, 0.31 mmol), Pd2(dba)3 (19 mg, 0.02 mmol), X-phos (23 mg, 0.04 mmol), and DIEA (122 mg, 0.94 mmol) were added. The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 120°C overnight. After the reaction, the reaction mixture was filtered through celite, and the filter cake was dried with an appropriate amount of ethyl acetate. The filtrate was added with water (30 mL) and extracted three times with ethyl acetate (60 mL). The organic phases were combined, washed twice with saturated brine (50.0 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. This was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 6.5 mg of the title compound 8. LC-MS (ESI): m / z 580.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.86 (d, J=6.0Hz, 1H), 7.79 (d, J=8.8Hz, 2H), 7.73 (d, J=2.0, 1H), 7.64-7.68 (m, 3H), 7.36-7.39 (m, 4H), 7.24 (dd, J=5.6, 2.4Hz, 1H), 4.44 (t, J=5.6Hz, 2H), 3.97 (t, J=5.6Hz, 2H), 1.71 (s, 6H), 1.65 (d, J=14.0Hz, 6H).

[0265] Example 27: Preparation of Compound 27

[0266] Preparation of compound 27-1

[0267] Compound 1-8 (250 mg, 0.59 mmol) was added to a three-necked flask, followed by anhydrous DCM (10 mL), (2-chloropyrimidin-5-yl)methanol (110 mg, 0.76 mmol), and N,N,N',N'-tetramethylazodicarbonamide (202 mg, 1.17 mmol). The atmosphere was replaced with nitrogen three times, and tributylphosphine (237 mg, 1.17 mmol) was added at 0°C. The reaction was stirred at 25°C for 3 hours. After completion of the reaction, water (20 ml) was added, and the mixture was extracted twice with DCM (20 mL). The organic phases were combined, dried, and concentrated to obtain the crude product, which was separated and purified by a normal phase silica gel column (EtOAc / PE = 0-30%) to obtain 150 mg of the title compound 27-1 in a 46% yield. LC-MS (ESI): 552.1 [M+H] + .

[0268] Preparation of compound 27

[0269] Compound 27-1 (100 mg, 0.18 mmol) was dissolved in DMF (2 mL) and tris(dibenzylideneacetone)dipalladium (17 mg, 0.02 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (21 mg, 0.04), DIEA (70 mg, 0.54 mmol), and 1-imino-1-oxothiolane (65 mg, 0.54 mmol) were added in sequence. The reaction system was stirred at 120°C for 3 hours. After the reaction, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 45 mg of the title compound 5. LC-MS (ESI): m / z 635.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.59 (s, 2H), 7.71 (d, J = 2.4Hz, 1H), 7.65 (d, J = 2.4Hz, 1H), 7.63-7.54 (m, 4H), 7.33-7.28 (m, 2H), 7.13-7.08 (m , 2H), 5.06 (s, 2H), 4.43 (t, J=5.6Hz, 2H), 3.97 (t, J=5.6Hz, 2H), 3.65-3.54 (m, 2H), 3.43-3.34 (m, 2H), 2.28-2.03 (m, 4H), 1.69 (s, 6H).

[0270] Example 28: Preparation of Compound 28

[0271] Preparation of compound 28

[0272] Compound 1-8 (200 mg, 0.47 mmol) was dissolved in DMF (5 mL) and 2-chloro-5-fluoropyrimidine (62 mg, 0.47 mmol) and potassium carbonate (138 mg, 0.94 mmol) were added sequentially. The reaction system was stirred at 50°C for 16 hours. After the reaction, the insoluble solid was filtered off, and the filtrate was added with water (30 mL) and extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. After purification by column chromatography (petroleum ether:ethyl acetate = 5:1), the crude product was obtained. This crude product was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 94 mg of the title compound 28. LC-MS (ESI): m / z 522.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.76 (s, 2H), 7.69-7.73 (m, 3H), 7.66 (d, J=2.4Hz, 1H), 7.62-7.64 (m, 2H) , 7.34-7.36 (m, 2H), 7.27-7.30 (m, 2H), 4.43 (m, J=5.6Hz, 2H), 3.96 (t, J=5.6Hz, 2H), 1.73 (s, 6H). 19 F NMR (376MHz, DMSO-d6) delta-147.83.

[0273] Example 29: Preparation of Compound 29

[0274] Preparation of compound 29-1

[0275] Compound 1-8 (200 mg, 0.47 mmol) was dissolved in DMF (5 mL), and 2-chloro-5-fluoropyrimidine (62 mg, 0.47 mmol) and potassium carbonate (138 mg, 0.94 mmol) were added sequentially. The reaction system was stirred at 50°C for 16 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was extracted three times with water (30 mL) and ethyl acetate (30 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by column chromatography (petroleum ether:ethyl acetate = 5:1) yielded 60 mg of the title compound 29-1.

[0276] Preparation of compound 29

[0277] Compound 29-1 (30 mg, 0.06 mmol) was dissolved in DMF (0.5 mL), and 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide hydrochloride (12 mg, 0.07 mmol) and potassium carbonate (54 mg, 0.17 mmol) were added sequentially. The reaction system was stirred at 60°C for 16 hours. After completion of the reaction, water (5 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted three times with ethyl acetate (5 mL). The organic phases were combined, washed once with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) and then by preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 20 mg of the title compound 29. LC-MS (ESI): m / z 649.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.38 (s, 2H), 7.71 (d, J=2.4Hz, 1H), 7.62-7.66 (m, 3H), 7.55-7.58 (m, 2H), 7.31-7.33 ( m, 2H), 7.00-7.04 (m, 2H), 4.53 (s, 4H), 4.43 (t, J=5.2Hz, 2H), 4.29 (s, 4H), 3.96 (t, J=5.2Hz, 2H), 1.69 (s, 6H).

[0278] Example 30: Preparation of Compound 30

[0279] Preparation of compound 30

[0280] Compound 29-1 (20 mg, 0.04 mmol) was dissolved in toluene (1 mL), and 19-1 (10 mg, 0.07 mmol), palladium acetate (1 mg, 0.004 mmol), cesium carbonate (24 mg, 0.07 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (4 mg, 0.007 mmol) were added in sequence. The reaction solution was nitrogen-purged three times and stirred at 105°C for 16 hours. After the reaction was completed, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. After purification by column chromatography (petroleum ether:ethyl acetate = 1:1), the crude product was obtained. This crude product was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 94 mg of the title compound 30. LC-MS (ESI): m / z 637.04 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.41 (s, 2H), 7.72 (d, J=2.4Hz, 1H), 7.63-7.68 (m, 3H), 7.57-7.59 (m, 2H), 7.32-7 .34(m, 2H), 7.07-7.11(m, 2H), 4.43(t, J=5.2Hz, 2H), 4.08-4.14(m, 2H), 3.94-4.00(m, 4H), 3.77-3.83(m 2H), 3.56-3.62(m, 2H), 1.69(s, 6H).

[0281] Example 31: Preparation of Compound 31

[0282] Preparation of compound 31-1

[0283] Compound 4-1 (300 mg, 0.70 mmol) was dissolved in DMF (3 mL), and 2-chloro-5-fluoropyrimidine (111 mg, 0.84 mmol) and potassium carbonate (194 mg, 1.41 mmol) were added sequentially. The reaction system was stirred at 50°C for 16 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was extracted twice with water (30 mL) and ethyl acetate (30 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by column chromatography (petroleum ether:ethyl acetate = 8:1) yielded 80 mg of the title compound 31-1. LC-MS (ESI): m / z 538.2 [M+H] + .

[0284] Preparation of compound 31

[0285] Compound 31-1 (30 mg, 0.06 mmol) was dissolved in toluene (1 mL), and 19-1 (15 mg, 0.11 mmol), palladium acetate (1 mg, 0.006 mmol), cesium carbonate (36 mg, 0.11 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg, 0.01 mmol) were added in sequence. The reaction mixture was nitrogen-purged three times and stirred at 105°C for 16 hours. After the reaction was completed, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. After purification by column chromatography (dichloromethane:methanol = 10:1), the crude product was obtained. This crude product was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 45% to 65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 12 mg of the title compound 31. LC-MS (ESI): m / z 637.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.41 (s, 2H), 7.70 (d, J = 2.0Hz, 1H), 7.64 (d, J = 2.0Hz, 1H), 7.59-7.61 (m, 2H), 7.40-7.47 (m, 2H), 7.29-7.34 (m, 3H), 6.96-6.99 (m, 1H), 4.42 (t, J=5.2Hz, 2H), 4.06-4.12 (m, 2H), 3.92-3.98 (m, 4H), 3.77-3.82 (m, 2H), 3.55-3.61 (m, 2H), 1.68 (s, 6H).

[0286] Example 32: Preparation of Compound 32

[0287] Preparation of compound 32

[0288] Compound 31-1 (20 mg, 0.04 mmol) was dissolved in DMF (0.5 mL) and 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide hydrochloride (10 mg, 0.06 mmol) and cesium carbonate (45 mg, 0.14 mmol) were added sequentially. The reaction solution was nitrogen-purged three times and stirred at 60°C for 16 hours. After completion of the reaction, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted twice with ethyl acetate (10 mL). The organic phases were combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. After purification by column chromatography (petroleum ether:ethyl acetate = 2:1), the crude product was obtained. This crude product was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 45% to 65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 3 mg of the title compound 32. LC-MS (ESI): m / z 649.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.38 (s, 2H), 7.71 (d, J = 2.4Hz, 1H), 7.64 (d, J = 2.4Hz, 1H), 7.56-7.58 (m, 2H), 7.35-7.44 (m, 2H), 7.31-7.34 ( m, 2H), 7.20 (t, J=2.0Hz, 1H), 6.89-6.92 (m, 1H), 4.52 (s, 4H), 4.42 (t, J=5.2Hz, 2H), 4.28 (s, 4H), 3.96 (t, J=5.2Hz, 2H), 1.68 (s, 6H).

[0289] Example 33: Preparation of Compound 33

[0290] Preparation of compound 33

[0291] Compound 28 (20 mg, 0.04 mmol) was dissolved in DMF (0.5 mL), and 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide hydrochloride (8 mg, 0.05 mmol) and cesium carbonate (25 mg, 0.08 mmol) were added sequentially. The reaction solution was stirred at 90°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, the insoluble solid was filtered out, and the filtrate was added with water (10 mL) and extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1), and then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile in 12 minutes; flow rate: 30 mL / min) to obtain 3 mg of the title compound 33. 1 H NMR (400MHz, DMSO-d6) δ8.76 (s, 2H), 7.73 (d, J = 2.3Hz, 1H), 7.71 (d, J = 8.6Hz, 2H), 7.66 (d, J = 2.3Hz, 1H), 7.63 (d, J = 8.4Hz, 2H), 7 .35 (d, J=8.4Hz, 2H), 7.29 (d, J=8.6Hz, 2H), 4.42 (s, 4H), 4.34 (t, J=5.1Hz, 2H), 4.30 (t, J=5.1Hz, 2H), 4.11 (s, 4H), 1.70 (s, 6H).

[0292] Example 34: Preparation of Compound 34

[0293] Preparation of compound 34-2

[0294] Compound 1-7 (300 mg, 0.62 mmol) was dissolved in 1,4-dioxane (20 mL) and water (5 mL). Compound 34-1 (170 mg, 0.75 mmol), potassium carbonate (258 mg, 1.87 mmol), and Pd(dppf)Cl2 (45 mg, 0.06 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the reaction system was stirred at 100°C for 4 hours. After completion of the reaction, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 30%) to obtain 290 mg of the title compound 34-2. LC-MS (ESI): m / z 458.2 [M+H] + .

[0295] Preparation of compound 34-3

[0296] Compound 34-2 (100 mg, 0.22 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperbenzoic acid (112 mg, 0.66 mmol) was added at 0°C. The reaction system was stirred at 25°C for 1 hour. After the reaction was completed, water (10 mL) was added and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed three times with saturated sodium carbonate solution (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product of the title compound 34-3, which was used directly in the next step without purification. LC-MS (ESI): m / z 490.0 [M+H] + .

[0297] Preparation of compound 34-4

[0298] Compound 34-3 (90 mg, 0.18 mmol) was dissolved in acetonitrile (20 mL), and (2-(methylthio)pyrimidin-4-yl)methanol (34 mg, 0.22 mmol) and potassium carbonate (75 mg, 0.54 mmol) were added sequentially. The reaction system was stirred at 70°C for 1 hour. After completion of the reaction, water (10 mL) was added and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 50%) to obtain 100 mg of the title compound 34-4. LC-MS (ESI): m / z 566.2 [M+H] + .

[0299] Preparation of compound 34-5

[0300] Compound 34-4 (100 mg, 0.18 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperbenzoic acid (91 mg, 0.54 mmol) was added at 0°C. The reaction system was stirred at 25°C for 1 hour. After the reaction was completed, water (10 mL) was added and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed three times with saturated sodium carbonate solution (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product of the title compound 34-5, which was used directly in the next step without purification. LC-MS (ESI): m / z 598.2 [M+H] + .

[0301] Preparation of compound 34

[0302] Compound 34-5 (100 mg, 0.17 mmol) was dissolved in acetonitrile (2.0 mL), and dimethylphosphine oxide (39 mg, 0.51 mmol) and potassium carbonate (69 mg, 0.51 mmol) were added sequentially. The reaction system was stirred at 80°C for 16 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative separation and purification (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 7.6 mg of the title compound 34. LC-MS (ESI): m / z 596.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.96-8.94 (m, 3H), 7.69 (d, J = 2.3Hz, 1H), 7.67 (d, J = 8.4Hz, 2H), 7.64 (d, J = 2.3Hz, 1H), 7.63-7.61 (m , 1H), 7.37 (d, J=8.4Hz, 2H), 5.63 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 3.95 (t, J=5.2Hz, 2H), 1.72 (d, J=13.8Hz, 6H), 1.69 (s, 6H). 31 P NMR (162MHz, Chloroform-d) δ34.23 (s, 1P).

[0303] Example 35: Preparation of Compound 35

[0304] Preparation of compound 35

[0305] Compound 34-5 (100 mg, 0.17 mmol) was dissolved in acetonitrile (2.0 mL), and 2-oxa-6-aza-spiro[3,3]heptane (50 mg, 0.51 mmol) and potassium carbonate (69 mg, 0.51 mmol) were added sequentially. The reaction system was stirred at 50°C for 1 hour. After completion of the reaction, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 38.6 mg of the title compound 35. LC-MS (ESI): m / z 617.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ 8.73 (s, 2H), 8.30 (d, J = 5.1Hz, 1H), 7.48 (d, J = 2.3Hz, 1H), 7.47 (d, J = 8.4Hz, 2H), 7.35 (d, J = 2.3Hz, 1H), 7.30 (d, J=8.4Hz, 2H), 6.78 (d, J=5.1Hz, 1H), 5.41 (s, 2H), 4.86 (s, 4H), 4.43 (t, J=6.1Hz, 2H), 4.30 (s, 4H), 3.88 (t, J=6.1Hz, 2H), 1.70 (s, 6H).

[0306] Example 36: Preparation of Compound 36

[0307] Preparation of compound 36-1

[0308] Compound 34-3 (290 mg, 0.59 mmol) was dissolved in acetonitrile (20 mL), and (2-chloropyrimidin-4-yl)methanol (102 mg, 0.71 mmol) and potassium carbonate (243 mg, 1.78 mmol) were added sequentially. The reaction system was stirred at 70°C for 1 hour. After completion of the reaction, water (10 mL) was added and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 50%) to obtain 250 mg of the title compound 36-1. LC-MS (ESI): m / z 554.2 [M+H] + .

[0309] Preparation of compound 36

[0310] Compound 36-1 (100 mg, 0.18 mmol) was dissolved in DMF (2 mL), and tris(dibenzylideneacetone)dipalladium (42 mg, 0.05 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (27 mg, 0.05 mmol), DIEA (68 mg, 0.54 mmol), and 1-imino-1-oxothiolane (43 mg, 0.36 mmol) were added in sequence. The reaction system was stirred at 100°C for 16 hours. After completion of the reaction, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 40%-60% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 36.3 mg of the title compound 36. LC-MS (ESI): m / z 637.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ 8.73 (s, 2H), 8.46 (d, J = 5.4Hz, 1H), 7.48 (d, J = 2.3Hz, 1H), 7.47 (d, J = 8.4Hz, 2H), 7.35 (d, J = 2.3Hz, 1H), 7.30 (d, J = 8.4Hz, 2H) ), 7.05 (d, J=5.4Hz, 1H), 5.50 (s, 2H), 4.44 (t, J=6.1Hz, 2H), 3.88 (t, J=6.1H z, 2H), 3.74-3.67 (m, 2H), 3.44-3.38 (m, 2H), 2.40-2.24 (m, 4H), 1.70 (s, 6H).

[0311] Example 37: Preparation of Compound 37

[0312] Preparation of compound 37-1

[0313] 2-Bromo-5-hydroxypyrimidine (500 mg, 2.86 mmol) was dissolved in dichloromethane (20 mL). (2-Methylthiopyrimidin-4-yl)methanol (538 mg, 3.42 mmol), N,N,N',N'-tetramethyl-azodicarbonamide (982 mg, 5.71 mmol), and tri-n-butylphosphine (1722 mg, 8.57 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the reaction system was stirred at 25°C for 4 hours. After completion of the reaction, water (10 mL) was added and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by column chromatography (PE:EA = 25%) afforded 600 mg of the title compound 37-1. LC-MS (ESI): m / z 313.0 [M+H] + .

[0314] Preparation of compound 37-2

[0315] Compound 37-1 (500 mg, 1.60 mmol) was dissolved in 1,4-dioxane (20 mL) and water (5 mL). Compound 12-3 (734 mg, 1.60 mmol), potassium carbonate (657 mg, 4.80 mmol), and Pd(dppf)Cl2 (117 mg, 0.16 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the reaction system was stirred at 100°C for 4 hours. After completion of the reaction, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 30%) to obtain 400 mg of the title compound 37-2. LC-MS (ESI): m / z 566.4 [M+H] + .

[0316] Preparation of compound 37-3

[0317] Compound 37-2 (100 mg, 0.18 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperbenzoic acid (91 mg, 0.54 mmol) was added at 0°C. The reaction system was stirred at 25°C for 1 hour. After the reaction was completed, water (10 mL) was added and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed three times with saturated sodium carbonate solution (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product of the title compound 37-3. It was used directly in the next step without purification. LC-MS (ESI): m / z 598.4 [M+H] + .

[0318] Preparation of compound 37

[0319] Compound 37-3 (100 mg, 0.17 mmol) was dissolved in acetonitrile (2.0 mL), and dimethylphosphine oxide (39 mg, 0.51 mmol) and potassium carbonate (69 mg, 0.51 mmol) were added sequentially. The reaction system was stirred at 80°C for 16 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative separation and purification (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 12 mg of the title compound 37. LC-MS (ESI): m / z 596.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ 8.95 (s, 1H), 8.56 (s, 2H), 8.30 (d, J = 8.4Hz, 2H), 7.71 (s, 1H), 7.45 (d, J = 2.4Hz, 1H), 7.38 (d, J = 2. 4Hz, 1H), 7.30 (d, J=8.4Hz, 1H), 5.38 (s, 2H), 4.42 (t, J=6.2Hz, 2H), 3.88 (t, J=6.2Hz, 2H), 1.91 (d, J=13.4Hz, 6H), 1.71 (s, 6H). 31 P NMR (162MHz, Chloroform-d) δ34.92 (s, 1P).

[0320] Example 38: Preparation of Compound 38

[0321] Preparation of compound 38

[0322] Compound 37-3 (100 mg, 0.17 mmol) was dissolved in acetonitrile (2.0 mL), and 2-oxa-6-aza-spiro[3,3]heptane (50 mg, 0.51 mmol) and potassium carbonate (69 mg, 0.51 mmol) were added sequentially. The reaction system was stirred at 50°C for 1 hour. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative separation and purification (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 32 mg of the title compound 38. LC-MS (ESI): m / z 617.3 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ 8.51 (s, 2H), 8.35 (d, J = 5.2Hz, 1H), 8.27 (d, J = 8.4Hz, 2H), 7.44 (d, J = 2.4Hz, 1H), 7.37 (d, J = 2.4Hz, 1H), 7.28 (d, J=8.4Hz, 2H), 6.81 (d, J=5.2Hz, 1H), 5.11 (s, 2H), 4.87 (s, 4H), 4.42 (t, J=6.1Hz, 2H), 4.36 (s, 4H), 3.87 (t, J=6.1Hz, 2H), 1.70 (s, 6H).

[0323] Example 39: Preparation of Compound 39

[0324] Preparation of compound 39-1

[0325] Compound (2-(methylthio)pyrimidin-4-yl)methanol (2.4 g, 15.36 mmol) was dissolved in dichloromethane (40 mL). Triethylamine (3.1 g, 30.72 mmol) was added, and the mixture was cooled to 0°C. MsCl (2.6 g, 23.04 mmol) was added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred for 2 hours. LCMS monitored the reaction completion, followed by concentration to remove the solvent, quenching with ice water (30 mL), and extraction with ethyl acetate (50 mL) three times. The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The concentrate was purified by column chromatography (ethyl acetate / petroleum ether = 0-100%) to afford 1.7 g of the title compound 39-1 in a 47.2% yield. LC-MS (ESI): m / z [M+H] +:235.1.

[0326] Preparation of compound 39-2

[0327] Compound 12-3 (1.2 g, 2.61 mmol) and 2-bromo-5-hydroxybenzonitrile (0.6 g, 2.87 mmol) were dissolved in 1,4-dioxane (25 mL). 1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (130 mg, 0.18 mmol) and a potassium carbonate aqueous solution (2 mol / L, 3.9 mL, 7.80 mmol) were added. The atmosphere was replaced with argon four times and heated to 110°C with stirring for 16 hours until the reaction was complete. The reaction system was cooled to room temperature and adjusted to weak acidity with 2 mol / L aqueous hydrochloric acid. The insoluble matter was filtered through a pad of Celite, and the filter cake was rinsed with ethyl acetate. The filtrates were combined and separated. The organic phase was washed once with saturated brine and dried over anhydrous sodium sulfate. The concentrated residue was purified by column chromatography (ethyl acetate / petroleum ether = 0-40%) to obtain 1.1 g of the title compound 39-2 in a yield of 93.5%. LC-MS (ESI): m / z [MH] - :449.1.

[0328] Preparation of compound 39-3

[0329] Compound 39-2 (400 mg, 0.89 mmol) and compound 39-1 (219 mg, 0.93 mmol) were dissolved in acetonitrile (8.0 mL). Cesium carbonate (580 mg, 1.78 mmol) was added at room temperature and stirred for 2 hours. LCMS confirmed the reaction was complete, and the mixture was filtered and the filter cake rinsed with ethyl acetate. The filtrates were combined and concentrated, and the resulting residue was purified by column chromatography (ethyl acetate / petroleum ether = 0-30%) to afford 480 mg of the title compound 39-3, in a 91.9% yield. LC-MS (ESI): m / z [M+Na] + :611.1.

[0330] Preparation of compound 39-4

[0331] Compound 39-3 (460 mg, 0.78 mmol) was dissolved in a mixture of THF (10 mL) and water (10 mL). Potassium peroxymonosulfate (1.92 g, 3.12 mmol) was added at room temperature and stirred for 16 hours. LCMS confirmed the reaction was complete. Water (30 mL) was added and the mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to yield 425 mg of the title compound 39-4, in an 87.6% yield.

[0332] Preparation of compound 39

[0333] Compound 39-4 (415 mg, 0.68 mmol) and dimethylphosphine oxide (532 mg, 6.80 mmol) were dissolved in acetonitrile (8 mL). Potassium carbonate (752.0 mg, 5.44 mmol) was added at room temperature and the mixture was heated to 85°C with stirring for 16 hours. LCMS analysis indicated that the reaction was nearly complete. The reaction was quenched with saturated brine (30 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by column chromatography (methanol / dichloromethane = 0-10%) to afford 130 mg of crude product, which was then purified by prep-HPLC (Waters 2767 / Qda, Column: XBridge XBridge C1819*250 mm, 10 μm; Mobile Phase A: 0.03% NH3H2O / H2O, B: ACN; flow rate: 20 ml / min; gradient: 59% to 59%; Retention Time: 9.2-10.7 min of 16 min) to afford 43.11 mg of the title compound 39. LC-MS (ESI): m / z [M+H] + :619.4. 1 H NMR (400MHz, DMSO-d6) δ9.02 (d, J=5.2Hz, 1H), 7.77 (dd, J=4.8, 3.2Hz, 1H), 7.74 (d, J=2.4Hz, 1H), 7.71 (d, J=2.8Hz, 1H), 7.68 (d, J=2.3Hz, 1H), 7.59 (d, J=8.8Hz, 1H), 7.52-7.48(m, 3H), 7.40(d, J=8.4Hz, 2H), 5.45(s, 2H), 4.43( t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 1.76 (d, J=13.6Hz, 6H), 1.72 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.04 (s, 1P).

[0334] Example 40: Preparation of Compound 40

[0335] Preparation of compound 40

[0336] Compound 4 (73.32 mg, 122.92 μmol) and THF (2 mL) were added to the reaction flask. 2-Oxa-6-azaspiro[3.3]heptane hydrochloride (20 mg, 147.50 μmol) and KCO (42.47 mg, 307.30 μmol) were then added at room temperature. The atmosphere was replaced with nitrogen three times and the reaction was continued at 80°C for 5 hours. LCMS monitoring confirmed the completion of the reaction, with the molecular ion peak of the desired product. The reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted three times with EA (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under reduced pressure. The crude product was purified by preparative liquid chromatography (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-60% acetonitrile over 30 minutes; flow rate: 30 mL / min) to obtain 26 mg of the title compound 40. LC-MS (ESI): m / z 615.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.35 (d, J=4.8Hz, 1H), 7.71 (d, J=2.4Hz, 1H), 7.65 (d, J=2. 4Hz, 1H), 7.60-7.64(m, 2H), 7.37(t, J=7.6Hz, 1H), 7.31-7.34(m, 2H), 7.27-7.28( m, 1H), 7.24-7.26 (m, 1H), 6.96-6.99 (m, 1H), 6.80 (d, J=5.2Hz, 1H), 5.08 (s, 2H), 4 .71 (s, 4H), 4.43 (t, J=5.2Hz, 2H), 4.20 (s, 4H), 3.96 (t, J=5.2Hz, 2H), 1.69 (s, 6H).

[0337] Example 41: Preparation of Compound 41

[0338] Preparation of compound 41

[0339] Compound 4 (54.13 mg, 90.75 μmol), THF (2 mL), 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide hydrochloride (20 mg, 108.90 μmol), and KCO (31.36 mg, 226.87 μmol) were added to a reaction flask. The atmosphere was replaced with nitrogen three times and the reaction was continued at 80°C for 5 hours. LCMS monitoring showed that the reaction was complete, with the molecular ion peak of the target product. The reaction solution was cooled to room temperature, water (30 mL) was added, and extraction was performed three times with EA (30 mL). The organic phases were combined, evaporated to dryness under reduced pressure, and purified using preparative HPLC (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-60% acetonitrile over 30 minutes; flow rate: 30 mL / min) to obtain 25 mg of the title compound 41. LC-MS (ESI): m / z 663.2 [M+H] + .1H NMR (400MHz, DMSO-d6) δ9.40 (d, J=5.2Hz, 1H), 7.71 (d, J=2.4Hz, 1H), 7.65 (d, J=2. 5Hz, 1H), 7.60-7.63(m, 2H), 7.37(t, J=8.0Hz, 1H), 7.31-7.35(m, 2H), 7.28-7.29( m, 1H), 7.24-7.27 (m, 1H), 6.97-7.00 (m, 1H), 6.86 (d, J=4.8Hz, 1H), 5.09 (s, 2H), 4 .50 (s, 4H), 4.43 (t, J=5.2Hz, 2H), 4.27 (s, 4H), 3.96 (t, J=5.2Hz, 2H), 1.69 (s, 6H).

[0340] Example 42: Preparation of Compound 42

[0341] Preparation of compound 42-2

[0342] Compound 42-1 (200 mg, 1.13 mmol) and 1-bromo-2-chloroethane (194.28 mg, 1.35 mmol, 112.76 μL) were weighed and dissolved in acetonitrile (10 mL). Cs2CO3 (735.65 mg, 2.26 mmol) was added. The reaction mixture was incubated at 80°C for 4 hours. LCMS showed the disappearance of the starting material and the formation of the product. The reaction mixture was poured into water and extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (EtOAc / PE: = 0-30%) to obtain 180 mg of the title compound 42-2, in a yield of 66.53%. LC-MS (ESI): m / z 240.2 [M+H] + .

[0343] Preparation of compound 42-3

[0344] Compound 42-2 (4.4 g, 18.36 mmol) was weighed and dissolved in tetrahydrofuran (50 mL). The mixture was replaced with N2 three times. Methylmagnesium bromide (3 M, 110.16 mmol, 36.72 mL) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 2 hours. LCMS showed that the starting material disappeared and the product was formed. The reaction mixture was poured into a saturated NH4Cl solution (50 mL). The mixture was extracted twice with ethyl acetate (200 mL + 150 mL). The organic phases were combined, washed with water (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (EtOAc / PE = 0-15%) to obtain 3.5 g of the title compound in a yield of 79.5%. LC-MS (ESI): m / z 240.2 [M+H] + .

[0345] Preparation of compound 42-4

[0346] Compound 42-3 and phenol (6.48 g, 68.84 mmol) were weighed and added to 1,2-dichloroethane (40 mL). Anhydrous aluminum chloride (3.67 g, 27.53 mmol) was then added. After three replacements with N2, the reaction mixture was stirred at 100°C for 3 hours. TLC showed the disappearance of the starting material and the formation of new spots. The reaction mixture was poured into water (40 mL). Extraction was performed twice with dichloromethane (60 mL + 40 mL). The organic phases were combined, washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (EtOAc / PE = 0-15%) to obtain 3.6 g of the title compound 42-4, in a yield of 82.8%. LC-MS (ESI): m / z 316.4 [M+H] + .

[0347] Preparation of compound 42-5

[0348] Compound 42-4 (1 g, 3.17 mmol) and triethylamine (961.28 mg, 9.50 mmol, 1.32 mL) were weighed and added to dichloromethane (15 mL). After N2 substitution three times, trifluoromethanesulfonic anhydride (1.07 g, 3.80 mmol, 639.30 μL) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 1 hour. LCMS showed the disappearance of the starting material and the formation of the product. The reaction mixture was evaporated to dryness under reduced pressure, and the resulting residue was purified by column chromatography (EtOAc / PE = 0-5%) to obtain 900 mg of the title compound 42-5, in a yield of 63.4%. LC-MS (ESI): m / z 448.2 [M+H] + .

[0349] Preparation of compound 42-6

[0350] To a 100 mL single-necked flask, add compound 42-5 (698.46 mg, 1.56 mmol), 4-hydroxyphenylboronic acid (236.62 mg, 1.72 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (114.11 mg, 155.96 μmol), potassium carbonate (538.85 mg, 3.90 mmol), dioxane (10 mL), and water (5 mL). The atmosphere was replaced with nitrogen three times and stirred at 90°C for 2 hours. LCMS indicated the reaction was complete, with the main peak being the molecular ion of the desired product. The reaction solution was evaporated to dryness under reduced pressure and purified by column chromatography (EA / PE = 0-15%) to obtain the title compound 42-6. LC-MS (ESI): m / z 392.2 [M+H] + .

[0351] Preparation of compound 42-7

[0352] 42-6 and 2-chloro-4-(chloromethyl)pyrimidine (228.77 mg, 1.40 mmol) were weighed and added to acetonitrile (8 mL). Potassium carbonate (352.66 mg, 2.55 mmol) was then added. The reaction mixture was stirred at 70°C for 3 hours. The reaction mixture was poured into water and extracted twice with dichloromethane (20 mL + 15 mL). The organic phases were combined, washed with water (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (EtOAc / PE = 0-15%) to obtain 540 mg of the title compound 42-7, in a yield of 81.6%. LC-MS (ESI): m / z 518.4 [M+H] + .

[0353] Preparation of compound 42

[0354] Compound 42-7 (100 mg, 192.89 μmol), dimethylphosphine oxide (45.16 mg, 578.66 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (22.32 mg, 38.58 μmol), and N,N-diisopropylethylamine (74.79 mg, 578.66 μmol, 100.79 μL) were weighed in DMF (3 mL). Tris(dibenzylideneacetone)dipalladium (17.66 mg, 19.29 μmol) was added. The reaction mixture was purged with N2 three times. The reaction mixture was microwaved at 120°C for 3 hours. LCMS showed the disappearance of the starting material and the formation of the product. The reaction solution was purified by preparative purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate Polar-RP 250×30 mm; column temperature: 25°C; gradient: 50%-70% acetonitrile over 8 minutes; flow rate: 50 mL / min) to obtain 41.8 mg of the title compound 42. LC-MS (ESI): m / z 560.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.00 (d, J=5.2Hz, 1H), 8.40 (d, J=2.4Hz, 1H), 8.19 (d, J= 2.0Hz, 1H), 8.17 (s, 1H), 7.73 (dd, J=5.2, 3.2Hz, 1H), 7.61 (d, J=8.8Hz, 2H), 7.5 5 (d, J=8.4Hz, 2H), 7.31 (d, J=8.4Hz, 2H), 7.14 (d, J=8.8HZ, 2H), 5.35 (s, 2H), 4. 75 (t, J=5.6Hz, 2H), 4.12 (t, J=5.6Hz, 2H), 1.76 (d, J=13.6Hz, 6H), 1.77 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.07 (s, 1P).

[0355] Example 43: Preparation of Compound 43

[0356] Preparation of compound 43

[0357] Compound 7-1 (200 mg, 0.36 mmol) was dissolved in DMF (2.0 mL) and tris(dibenzylideneacetone)dipalladium (33 mg, 0.04 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (42 mg, 0.07), DIEA (94 mg, 0.7 mmol), and 1,4-oxathiazolesulfenyl imide (73 mg, 0.54 mmol) were added in sequence. The reaction system was stirred at 100°C for 16 hours. After the reaction, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted with dichloromethane (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) afforded 82 mg of the title compound 43. LC-MS (ESI): m / z 651.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.46 (d, J=5.0Hz, 1H), 7.71 (d, J=2.3Hz, 1H), 7.64 (d, J=2.3Hz, 1 H), 7.60 (d, J=8.8Hz, 2H), 7.56 (d, J=8.4Hz, 2H), 7.30 (d, J=8.4Hz, 2H), 7.07 (d, J=8.8Hz , 2H), 7.00 (d, J=5.0Hz, 1H), 5.12 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 4.05-4.09 (m, 2H), 3.96 (t, J=5.2Hz, 2H), 3.97-3.93 (m, 2H), 3.80-3.74 (m, 2H), 3.59-3.54 (m, 2H), 1.68 (s, 6H).

[0358] Example 44: Preparation of Compound 44

[0359] Preparation of compound 44

[0360] Compound 7-1 (200 mg, 0.36 mmol) was dissolved in DMF (2.0 mL) and tris(dibenzylideneacetone)dipalladium (33 mg, 0.04 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (42 mg, 0.07), DIEA (94 mg, 0.7 mmol), and dimethylsulfenyl imide (51 mg, 0.54 mmol) were added in sequence. The reaction system was stirred at 100°C for 16 hours. After the reaction, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) afforded 17 mg of the title compound 44. LC-MS (ESI): m / z 609.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.45 (d, J=5.1Hz, 1H), 7.70 (d, J=2.4Hz, 1H), 7.64 (d, J=2.4Hz, 1H), 7.60 (d, J=8.8Hz, 2H), 7.55 (d, J=8.5Hz, 2H), 7.30 (d , J=8.5Hz, 2H), 7.07 (d, J=8.8Hz, 2H), 6.95 (d, J=5.1Hz, 1H), 5.10 (s, 2H) , 4.42 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 3.40 (s, 6H), 1.68 (s, 6H).

[0361] Example 45: Preparation of Compound 45

[0362] Preparation of compound 45

[0363] Compound 42-7 (80 mg, 154.31 μmol) and 2-oxa-6-azaspiro[3.3]heptane (16.83 mg, 169.74 μmol) were weighed in ethanol (2 mL), and triethylamine (46.84 mg, 462.93 μmol, 64.57 μL) was added. The atmosphere was purged with nitrogen three times. The reaction solution was microwave-heated at 80°C for 3 hours. LCMS showed the disappearance of the starting material and the formation of the product. The reaction solution was purified by preparative chromatography (Preparative Method: Column: Pntulips ZZ-C18 10 μm 250 x 20 mm; Column temperature: 25°C; Mobile phase: Water (0.1% FA)-Acetonitrile; Gradient elution of the mobile phase: 50%-70% acetonitrile over 8 minutes, 70%-90% acetonitrile over 4 minutes; Flow rate: 30 mL / min) to yield 42 mg of the title compound 45. LC-MS (ESI): m / z 582.2 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ8.39 (d, J=2.3Hz, 1H), 8.35 (d, J=5.0Hz, 1H), 8.18 (d, J =2.3Hz, 1H), 8.17 (s, 1H), 7.58 (d, J = 8.8Hz, 2H), 8.54 (d, J = 8.4Hz, 2H), 7.31 (d , J=8.4Hz, 2H), 7.06 (d, J=8.8Hz, 2H), 6.76 (d, J=5.0Hz, 1H), 5.04 (s, 2H), 4.75 (t, J=5.8Hz, 2H), 4.72 (s, 4H), 4.21 (s, 4H), 4.12 (t, J=5.8Hz, 2H), 1.77 (s, 6H).

[0364] Example 46: Preparation of Compound 46

[0365] Preparation of compound 46

[0366] Compound 42-7 (80 mg, 154.31 μmol) and 1-aminotetrahydrothiophene-1-oxide (27.59 mg, 231.47 μmol) were weighed in DMF (2 mL). Tris(dibenzylideneacetone)dipalladium (14.13 mg, 15.43 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17.86 mg, 30.86 μmol), and triethylamine (46.84 mg, 462.93 μmol, 64.57 μL) were added. The reaction mixture was heated in a microwave at 120°C for 3 hours. LCMS showed the disappearance of the starting material and the formation of the product. The reaction solution was purified by preparative chromatography (chromatographic column: Pntulips ZZ-C18 10 μm 250 x 20 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; gradient elution of the mobile phase with acetonitrile from 50% to 70% over 8 minutes; flow rate: 30 mL / min) to obtain 24.5 mg of the title compound 46. LC-MS (ESI): m / z 601.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.46 (d, J=5.0, 1H), 8.39 (d, J=2.3Hz, 1H), 8.18 (d, J=2.2Hz, 1H), 8 .17 (s, 1H), 7.58 (d, J = 8.8Hz, 2H), 7.54 (d, J = 8.5Hz, 2H), 7.31 (d, J = 8.5Hz, 2H), 7.07 (d, J = 8.8Hz, 2H), 6.98 (d, J=5.0Hz, 1H), 5.10 (s, 2H), 4.75 (t, J=5.8Hz, 2H), 4.12 (t, J=5.8Hz, 2H ), 3.61-3.54(m, 2H), 3.39-3.32(m, 2H), 2.26-2.17(m, 2H), 2.11-2.04(m, 2H), 1.77(s, 6H).

[0367] Example 47: Preparation of Compound 47

[0368] Preparation of compound 47

[0369] Compound 42-7 (100 mg, 192.89 μmol) and methanesulfonamide (36.70 mg, 385.78 μmol) were weighed in acetonitrile (3 mL), and cesium carbonate (125.69 mg, 385.78 μmol, 173.25 μL) was added. The reaction mixture was stirred at 80°C for 3 hours. LCMS showed the disappearance of the starting material and the formation of the product. The reaction mixture was purified by preparative purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate Polar-RP 250×30 mm; column temperature: 25°C; gradient: 60%-80% acetonitrile over 8 minutes; flow rate: 50 mL / min) to obtain 6.1 mg of the title compound 47. LC-MS (ESI): m / z 577.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.40 (d, J=2.2Hz, 1H), 8.36 (m, 2H), 8.18 (d, J=2.4Hz, 1H), 7.58 (d, J=8.8Hz, 2H), 7.54 (d, J=8.5Hz, 2H), 7.31 (d, J =8.5Hz, 2H), 7.07 (d, J = 8.8Hz, 2H), 6.83 (br.s, 2H), 5.04 (s, 2H), 4.75 (t, J = 5.8Hz, 2H), 4.13 (t, J = 5.8Hz, 2H), 3.08 (s, 3H), 1.77 (s, 6H).

[0370] Example 48: Preparation of Compound 48

[0371] Preparation of compound 48-1

[0372] Compound 1-8 (260 mg, 0.62 mmol), compound 9-1 (145 mg, 0.72 mmol), and N,N,N',N'-tetramethylazodicarbonamide (215 mg, 1.24 mmol) were dissolved in dichloromethane (20 mL), and tributylphosphine (375 mg, 1.86 mmol) was added. The reaction system was stirred at 25°C for 1 hour. After the reaction, water (10 mL) was added and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 30%) to obtain 200 mg of the title compound 48-1. LC-MS (ESI): m / z 553.2 [M+H-tBu] + .

[0373] Preparation of compound 48-2

[0374] Compound 48-1 (200 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL) and a 4 M solution of hydrogen chloride in 1,4-dioxane (10 mL) was added at 0°C. The reaction system was stirred at 25°C for 1 hour. After the reaction, the solvent was directly removed by spin drying to obtain crude product 48-2. This product was used directly in the next step without purification. LC-MS (ESI): m / z 509.2 [M+H] + .

[0375] Preparation of compound 48-3

[0376] Compound 48-2 (200 mg, 0.39 mmol) was dissolved in methanol (10 mL), and 4-chloro-2-(methylsulfonyl)pyrimidine (89 mg, 0.47 mmol) and triethylamine (79 mg, 0.78 mmol) were added sequentially. The reaction system was stirred at 25°C for 1 hour. After completion of the reaction, water (10 mL) was added and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 60%) to obtain 200 mg of the title compound 48-3. LC-MS (ESI): m / z 665.2 [M+H] + .

[0377] Preparation of compound 48

[0378] Compound 48-3 (100 mg, 0.15 mmol) was dissolved in acetonitrile (5 mL), and dimethylphosphine oxide (35 mg, 0.45 mmol) and potassium carbonate (62 mg, 0.45 mmol) were added sequentially. The reaction system was stirred at 80°C for 16 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative separation and purification (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 37.8 mg of the title compound 48. LC-MS (ESI): m / z 663.3 [M+H] + . 1H NMR (400MHz, Chloroform-d) δ8.29 (d, J=6.1Hz, 1H), 7.53 (d, J=8.6Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 7.49 (d, J=2.3Hz, 1H), 7.37 (d, J=2.3Hz, 1H), 7.23 (d, J=8.4Hz, 2H), 7. 00(d, J=8.6Hz, 2H), 6.62(br.s, 1H), 4.68(br.s, 1H), 4.43(t, J=6.2Hz, 2H), 3.91(m , 4H), 3.88 (t, J=6.2Hz, 2H), 2.06-1.95 (m, 4H), 1.88 (d, J=13.5Hz, 6H), 1.70 (s, 6H). 31 P NMR (162MHz, Chloroform-d) δ 35.95 (s, 1P).

[0379] Example 49: Preparation of Compound 49

[0380] Preparation of compound 49-1

[0381] Compound 1-7 (1 g, 2.07 mmol) was dissolved in DMF (10 mL), and tris(dibenzylideneacetone)dipalladium (190 mg, 0.21 mmol), 1,1′-binaphthyl-2,2′-bisdiphenylphosphine (240 mg, 0.42 mmol), cesium carbonate (536 mg, 4.15 mmol), and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (493 mg, 2.49 mmol) were added in sequence. The reaction system was stirred at 70°C for 16 hours. After completion of the reaction, water (10 mL) was added, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by column chromatography (PE / EA = 30%) to obtain 560 mg of the title compound 49-1. LC-MS (ESI): m / z 530.0 [M+H] + .

[0382] Preparation of compound 49-2

[0383] Compound 49-1 (560 mg, 1.06 mmol) was dissolved in a solution of methanolic hydrochloric acid (4N, 3.0 mL, 12 mmol), and the reaction system was stirred at room temperature for 3 hours. After completion of the reaction, water (10 mL) was added and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 500 mg of crude product of the title compound 49-2. LC-MS (ESI): m / z 430.0 [M+H] + .

[0384] Preparation of compound 49-3

[0385] Compound 49-2 (300 mg, 0.70 mmol) was dissolved in acetonitrile (10 mL), and 2-chloro-4-(chloromethyl)pyrimidine (171 mg, 1.05 mmol) and cesium carbonate (682 mg, 2.10 mmol) were added sequentially. The reaction system was stirred at 25°C for 1 hour. After completion of the reaction, water (10 mL) was added and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 70%) to obtain 200 mg of the title compound 49-3. LC-MS (ESI): m / z 556.2 [M+H] + .

[0386] Preparation of compound 49

[0387] Compound 49-3 (100 mg, 0.18 mmol) was dissolved in DMF (5.0 mL), and dimethylphosphine oxide (42 mg, 0.54 mmol), DIPEA (70 mg, 0.54 mmol), tris(dibenzylidene-base acetone)dipalladium (18 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27 mg, 0.05 mmol) were added sequentially. The reaction system was stirred at 80°C for 16 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was added with water (10 mL). The mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 40%-60% acetonitrile over 12 minutes; flow rate: 30 mL / min) afforded 6 mg of the title compound 49. LC-MS (ESI): m / z 598.2 [M+H] + . 1H NMR (400MHz, Chloroform-d) δ8.82 (d, J=5.1Hz, 1H), 7.49 (dd, J=5.1, 3.3Hz, 1H), 7.44 (d, J=2.4Hz, 1H), 7.29 (d, J=2.3Hz, 1H), 7.02 (d, J=8.6Hz, 2H ), 6.40 (d, J=8.6Hz, 2H), 4.40 (t, J=6.2Hz, 2H), 3.99 (s, 4H), 3.93 (s, 2H) , 3.87 (t, J=6.2Hz, 2H), 3.68 (s, 4H), 1.89 (d, J=13.6Hz, 6H), 1.61 (s, 6H). 31 P NMR (162MHz, Chloroform-d) δ36.12 (s, 1P).

[0388] Example 50: Preparation of Compound 50

[0389] Preparation of compound 50

[0390] Compound 49-3 (100 mg, 0.18 mmol) was dissolved in DMF (5 mL), and 1-aminotetrahydrothiophene-1-oxide (42 mg, 0.54 mmol), DIPEA (70 mg, 0.54 mmol), tris(dibenzylidene-base acetone)dipalladium (18 mg, 0.02 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (27 mg, 0.05 mmol) were added sequentially. The reaction system was stirred at 80°C for 16 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was added with water (10 mL). The mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 40%-60% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 4.7 mg of the title compound 50. LC-MS (ESI): m / z 639.2 [M+H] + . 1H NMR (400MHz, Chloroform-d) δ 8.48 (d, J = 5.0Hz, 1H), 7.43 (d, J = 2.4Hz, 1H), 7.28 (d, J = 2.4Hz, 1H), 7.01 (d, J = 8.6Hz, 2H), 6.94 (d, J = 5.0Hz, 1H), 6.38 (d , J=8.6Hz, 2H), 4.40 (t, J=6.2Hz, 2H), 4.03-3.97 (m, 8H), 3.87 (t, J=6.2Hz, 2H), 3.75-3.66(m, 2H), 3.49-3.42(m, 2H), 2.37-2.27(m, 4H), 1.61(s, 6H).

[0391] Example 51: Preparation of Compound 51

[0392] Preparation of compound 51-1

[0393] Compound 4-1 (250 mg, 0.59 mmol) was added to a three-necked flask, followed by anhydrous DCM (10 mL), (2-chloropyrimidin-5-yl)methanol (110 mg, 0.76 mmol), and N,N,N′,N′-tetramethylazodicarbonamide (202 mg, 1.17 mmol). The atmosphere was replaced with nitrogen three times, and tributylphosphine (237 mg, 1.17 mmol) was added at 0°C. The reaction was stirred at 25°C for 3 hours. After completion of the reaction, water (20 ml) was added, and the mixture was extracted twice with DCM (20 mL). The organic phases were combined, dried, and concentrated to obtain the crude product, which was separated and purified by a normal phase silica gel column (EtOAc / PE = 0-30%) to obtain 150 mg of the title compound 51-1 in a 46% yield. LC-MS (ESI): 552.2 [M+H] + .

[0394] Preparation of compound 51

[0395] Compound 51-1 (100 mg, 0.18 mmol) was dissolved in DMF (2.0 mL), and tris(dibenzylideneacetone)dipalladium (17 mg, 0.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21 mg, 0.04), DIEA (70 mg, 0.54 mmol), and dimethylphosphine oxide (42 mg, 0.54 mmol) were added sequentially. The reaction system was stirred at 120°C in a microwave oven for 3 hours. After completion of the reaction, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 54 mg of the title compound 51. LC-MS (ESI): m / z 594.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 2H), 7.71 (d, J = 2.3Hz, 1H), 7.65 (d, J = 2.3Hz, 1 H), 7.62 (d, J=8.6Hz, 2H), 7.40 (t, J=7.9Hz, 1H), 7.34 (d, J=8.6Hz, 2H), 7.34-7 .32 (m, 1H), 7.27 (d, J=8.0Hz, 1H), 7.05 (dd, J=8.2, 2.5Hz, 1H), 5.34 (s, 2H), 4. 42 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 1.77 (d, J=13.7Hz, 6H), 1.69 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.04 (s, 1P).

[0396] Example 52: Preparation of Compound 52

[0397] Preparation of compound 52

[0398] Compound 31-1 (30 mg, 0.06 mmol) was added to a microwave tube and dissolved in dioxane (0.5 mL). Dimethylphosphine oxide (7 mg, 0.07 mmol), tris(dibenzylideneacetone)dipalladium (5 mg, 0.006 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg, 0.01 mmol), and N,N-diisopropylethylamine (24 mg, 0.19 mmol) were added in sequence. The reaction solution was stirred at 120°C under a nitrogen atmosphere for 16 hours. After the reaction was completed, the insoluble matter was filtered off, water (5 mL) was added, and the mixture was extracted three times with ethyl acetate (5 mL). The organic phases were combined, washed once with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (dichloromethane:methanol = 10:1) and then by preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 10 mg of the title compound 52. LC-MS (ESI): m / z 580.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.79 (s, 2H), 7.70 (d, J = 2.3Hz, 1H), 7.65 (d, J = 8.5Hz, 2H), 7.64 (d, J = 2.4Hz, 1H), 7.58-7.52 (m, 3H), 7.34 (d, J=8.5Hz, 2H), 7.21-7.18 (m, 1H), 4.42 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 1.75 (d, J=13.8Hz, 6H), 1.69 (s, 6H).

[0399] Example 53: Preparation of Compound 53

[0400] Preparation of compound 53

[0401] Compound 7-1 (100 mg, 180.87 μmol) and compound 53-1 (34.15 mg, 198.96 μmol) were dissolved in acetonitrile (2 mL), and triethylamine (54.91 mg, 542.62 μmol, 75.68 μL) was added. The reaction mixture was purged with nitrogen three times and heated in a microwave oven at 80°C for 2 hours. LCMS analysis showed the disappearance of the starting material and the formation of the product. The reaction mixture was purified by preparative chromatography (Preparative Method: Column: Pntulips ZZ-C18 10 μm 250 x 20 mm; Column temperature: 25°C; Mobile phase: Water (0.1% FA)-Acetonitrile; Acetonitrile ratio in the mobile phase: 50%-70% within 8 minutes, 70%-90% within 4 minutes, and 95%-95% within 4 minutes; Flow rate: 30 mL / min) to yield 40 mg of the title compound 53. LC-MS (ESI): m / z 651.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.42 (d, J=5.0Hz, 1H), 7.71 (d, J=2.4Hz, 1H), 7.64 (d, J=2.4Hz, 1H), 7.60 (d, J=8.8Hz, 2H), 7.56 (d, J=8.4Hz, 2H), 7.30 (d, J=8.0Hz, 2H), 7.08 (d, J=8.8H z, 2H), 6.86 (d, J=5.0Hz, 1H), 5.09 (s, 2H), 4.42 (t, J=5.1Hz, 2H), 4.41-4.39 (m, 1H), 4. 34 (t, J=8.4Hz, 2H), 4.25-4.22 (m, 2H), 3.96 (t, J=5.1Hz, 2H), 3.07 (s, 3H), 1.68 (s, 6H).

[0402] Example 54: Preparation of Compound 54

[0403] Preparation of compound 54

[0404] Compound 7-1 (100 mg, 180.87 μmol) and compound 54-1 (21.80 mg, 198.96 μmol) were dissolved in acetonitrile (2 mL), and triethylamine (54.91 mg, 542.62 μmol, 75.68 μL) was added. The reaction solution was purged with nitrogen three times and heated in a microwave oven at 80°C for 2 hours. LCMS showed the disappearance of the starting material and the formation of the product. The reaction solution was purified by preparative purification (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate Polar-RP 250×30 mm; column temperature: 25°C; gradient: acetonitrile 70%-90% over 8 minutes; flow rate: 50 mL / min) to obtain 54.9 mg of the title compound 54. LC-MS (ESI): m / z 589.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.34 (d, J=5.0, 1H), 7.70 (d, J=2.3Hz, 1H), 7.63 (d, J=2.3Hz, 1H), 7.59 (d, J=8.8Hz, 2H), 7.55 (d, J=8.5Hz, 2H), 7.30 (d, J=8.5Hz, 2H), 7.07 (d, J=8.8Hz, 2H) , 6.74 (d, J=5.0Hz, 1H), 5.71 (s, 1H), 5.04 (s, 2H), 4.56 (s, 1H), 4.42 (t, J=5.2Hz, 2H), 4.2 4 (dd, J=9.3, 6.6Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 3.79 (dd, J=9.6, 4.5Hz, 2H), 1.68 (s, 6H).

[0405] Example 55: Preparation of Compound 55

[0406] Preparation of compound 55

[0407] Compound 7-1 (100 mg, 180.87 μmol) and compound 55-1 (24.59 mg, 198.96 μmol) were dissolved in acetonitrile (3 mL), and triethylamine (54.91 mg, 542.62 μmol, 75.68 μL) was added. The reaction mixture was stirred at 80°C for 3 hours. LCMS showed the disappearance of the starting material and the formation of the product. The reaction mixture was subjected to preparative purification (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate Polar-RP 250× 30 mm; column temperature: 25°C; gradient elution: 80%-95% acetonitrile over 8 minutes; flow rate: 50 mL / min) to obtain 65.7 mg of the title compound 55. LC-MS (ESI): m / z 603.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 8.36 (d, J = 5.0Hz, 1H), 7.70 (d, J = 2.3Hz, 1H), 7.64 (d, J = 2.3Hz, 1H ), 7.59 (d, J=8.8Hz, 2H), 7.55 (d, J=8.4Hz, 2H), 7.30 (d, J=8.4Hz, 2H), 7.07 (d, J=8.8Hz, 2 H), 6.77 (d, J=5.0Hz, 1H), 5.05 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 4.34-4.29 (m, 1H), 4.25-4. 21 (m, 2H), 3.96 (t, J=5.2Hz, 2H), 3.85 (dd, J=10.0, 3.9Hz, 2H), 3.25 (s, 3H), 1.68 (s, 6H).

[0408] Example 56: Preparation of Compound 56

[0409] Preparation of compound 56-1

[0410] Compound 12-3 (1.30 g, 2.82 mmol) and 5-bromo-2-hydroxybenzonitrile (0.73 g, 3.67 mmol) were dissolved in 1,4-dioxane (13 mL). 1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (210 mg, 0.28 mmol) and aqueous potassium carbonate (2 mol / L, 4.20 mL, 7.80 mmol) were added. The atmosphere was purged with argon four times and heated to 110°C with stirring for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, acidified with aqueous hydrochloric acid (2.0 M), and filtered through Celite. The filter cake was rinsed with ethyl acetate. The filtrates were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by column chromatography (ethyl acetate / petroleum ether = 0-50%) to afford 1.0 g of the title compound 56-1 in a yield of 72%. LC-MS (ESI): m / z [MH]-: 449.2.

[0411] Preparation of compound 56-2

[0412] Compound 56-1 (800 mg, 1.77 mmol) and compound 39-1 (456.18 mg, 1.95 mmol) were dissolved in acetonitrile (16 mL). Cesium carbonate (1.15 g, 3.54 mmol) was added at room temperature and the mixture was heated to 80°C and stirred for 2 hours. LCMS indicated the reaction was complete. The mixture was filtered and the filter cake was rinsed with ethyl acetate. The filtrates were combined and evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate / petroleum ether = 0-30%) to afford 800 mg of the title compound 56-2 in a yield of 73.5%. LC-MS (ESI): m / z [M+H] + :589.1.

[0413] Preparation of compound 56-3

[0414] Compound 56-2 (188 mg, 0.32 mmol) was dissolved in acetone (4.0 mL). Sodium tungstate (10 mg, 0.032 mmol) and hydrogen peroxide (218 mg, 1.92 mmol, 30%) were added sequentially at room temperature. The mixture was heated to 40°C and stirred for 16 hours. LCMS analysis showed that the reaction was complete. Aqueous sodium sulfite solution (30 mL) was added at 0°C, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 200 mg of the crude title compound 56-3, which was used directly in the next step without purification. LC-MS (ESI): m / z [M+H] + :620.8.

[0415] Preparation of compound 56

[0416] Compound 56-3 (200 mg, 0.32 mmol) and dimethylphosphine oxide (125 mg, 1.60 mmol) were dissolved in acetonitrile (4.0 mL). Potassium carbonate (177 mg, 1.28 mmol) was added at room temperature and the mixture was heated to 85°C with stirring for 2 hours. LCMS analysis indicated approximately 2% product and 71% starting material. Additional N,N-dimethylacetamide (4.0 mL) was added. The reaction was stirred at 85°C overnight. LCMS analysis indicated the reaction was complete. The mixture was cooled to room temperature, saturated brine (30 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by column chromatography (methanol / dichloromethane = 0-10%) to give 120 mg of crude product. This was then purified by prep-HPLC (Waters 2767 / Qda, Column: XBridge XBridge C18 19*250 mm, 10 μm; mobile phase A: 0.03% NH3H2O / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 70% mobile phase B over 16 minutes; target compound collection period: 8.0-9.2 minutes) to give 18 mg of the title compound 56. LC-MS (ESI): m / z 619.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.75 (d, J=5.7Hz, 1H), 8.29 (d, J=1.6Hz, 1H), 7.78 (dd, J=8 .7, 1.9Hz, 1H), 7.72 (d, J=2.3Hz, 1H), 7.66 (d, J=8.5Hz, 2H), 7.66-7.64 (m, 1H), 7.6 1 (d, J=8.7Hz, 1H), 7.53 (dd, J=5.6, 3.3Hz, 1H), 7.39 (d, J=8.5Hz, 2H), 6.87 (s, 2H) , 4.43 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 1.80 (d, J=13.6Hz, 6H), 1.71 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ33.51 (s, 1P).

[0417] Example 57: Preparation of Compound 57

[0418] Preparation of compounds 57-1 and 57-2

[0419] Compound 4-1 (255.80 mg, 0.60 mmol) was dissolved in acetonitrile (6 mL), and 4-chloro-2-(methylsulfonyl)pyrimidine (115.57 mg, 0.60 mmol) and potassium carbonate (165.85 mg, 1.20 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the reaction system was stirred at 25°C for 5 hours. After the reaction, water (10 mL) was added, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 30%) to obtain 180 mg of the title compound 57-1. LC-MS (ESI): m / z 582.2 [M+H] + and 100 mg of the title compound 57-2, LC-MS (ESI): m / z 538.2 [M+H] + .

[0420] Preparation of compound 57

[0421] Compound 57-1 (30.5 mg, 52.43 μmol) was dissolved in DMF (2 mL). Cs2CO3 (34.2 mg, 104.87 μmol) and 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide hydrochloride (10.59 mg, 57.68 μmol) were added sequentially. The reaction system was stirred at 25°C for 2 hours. After completion of the reaction, the insoluble solid was filtered off and the product was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 5.5 mg of the title compound 57. LC-MS (ESI): m / z 649.2 [M+H] + . 1 H NMR (400MHz, CDC13) δ8.18 (d, J=5.6Hz, 1H), 7.45-7.54 (m, 5H), 7.34-7.35 (m, 2H), 7.25-7.27 (m, 2H), 7.09-7. 12 (m, 1H), 6.20 (d, J=5.6Hz, 1H), 4.43 (t, J=6.4Hz, 2H), 4.33-4.35 (m, 8H), 3.88 (t, J=6.4Hz, 2H), 1.70 (s, 6H).

[0422] Example 58: Preparation of Compound 58

[0423] Preparation of compound 58

[0424] Compound 57-2 (28.25 mg, 52.43 μmol) was dissolved in DMF (2 mL), and Cs2CO3 (34.17 mg, 104.87 μmol) and 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide hydrochloride (10.59 mg, 57.68 μmol) were added sequentially. The reaction system was stirred at 25°C for 2 hours. After completion of the reaction, the insoluble solid was filtered off and the product was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 8 mg of the title compound 58. LC-MS (ESI): m / z 649.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.07 (br.s, 1H), 7.52 (d, J=8.0Hz, 2H), 7.48 (d, J=2.4Hz, 1H), 7.45-7.46 (m, 2H), 7.38 (s, 1H), 7.36 (d, J=2.4Hz, 1H), 7.24 (d, J=7.6Hz, 2H), 7.15 (s, 1H), 6.01 (br.s, 1H), 4.42 (t, J=5.2Hz, 2H), 4.35-4.39 (m, 8H), 3.88 (t, J=5.2Hz, 2H), 1.69 (s, 6H).

[0425] Example 59: Preparation of Compound 59

[0426] Preparation of compound 59

[0427] Compound 57-1 (30.54 mg, 52.43 μmol) was dissolved in DMF (2 mL), and Cs2CO3 (34.17 mg, 104.87 μmol) and 2-oxa-6-azaspiro[3.3]heptane (7.82 mg, 57.68 μmol) were added sequentially. The reaction system was stirred at 25°C for 2 hours. After completion of the reaction, the insoluble solid was filtered off and the product was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 7.5 mg of the title compound 59. LC-MS (ESI): m / z 601.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.15 (d, J=6.0Hz, 1H), 7.53 (d, J=8.0Hz, 2H), 7.45-7.48 (m, 3H), 7.35-7.36 (m, 2H), 7.25-7.27 (m, 2H), 7.10-7.13 (m, 1H), 6.09 (d, J=5.6, 1H), 4.82 (s, 4H), 4.43 (t, J=5.6Hz, 2H), 4.27 (s, 4H), 3.88 (t, J=5.6Hz, 2H), 1.70 (s, 6H).

[0428] Example 60: Preparation of Compound 60

[0429] Preparation of Compound 60

[0430] Compound 57-1 (58.3 mg, 100.09 μmol) was dissolved in acetonitrile (2 mL), and Cs2CO3 (65.22 mg, 200.17 μmol) and 1,4-oxathiinanesulfenyl imide (27.06 mg, 200.17 μmol) were added sequentially. The reaction system was stirred at 120°C in a microwave oven for 1 hour. After completion of the reaction, the insoluble solid was filtered off and the product was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 3.5 mg of the title compound 60. LC-MS (ESI): m / z 637.2 [M+H] + . 1 H NMR (400MHz, CDC13) δ8.35 (d, J=3.6Hz, 1H), 7.54 (d, J=8.0Hz, 2H), 7.50-7.45 (m, 3H), 7.36-7.35 (m, 2H), 7.26-7.24 (m, 2H), 7.13 (d, J=6.6Hz, 1H), 6.46 (d, J=5.7Hz, 1H), 4.43 (t, J=6.2Hz, 2H), 4.03-3.95 (m, 4H), 3. 88 (t, J=6.2Hz, 2H), 3.55-3.48 (m, 2H), 3.23-3.13 (m, 2H), 1.69 (s, 6H).

[0431] Example 61: Preparation of Compound 61

[0432] Preparation of compound 61-2

[0433] Under nitrogen, dimethylphosphine oxide (966 mg, 12.38 mmol) was dissolved in THF (20 mL). NaHMDS (2 M, 12.38 mmol, 6.2 mL) was added dropwise at 0°C, and the temperature was slowly raised to room temperature with stirring for 1 hour. After cooling the system to 0°C, a solution of 61-1 (2 g, 6.19 mmol) in THF (5 mL) was added dropwise. The temperature was slowly raised to room temperature and stirred for 48 hours. The system was directly spin-dried, and ethyl acetate (20 mL) was added and stirred for 1 hour. The filtrate was then filtered and spin-dried. The crude product was purified by column chromatography (EA / PE = 0-10%) to afford 580 mg of the target compound 61-2, in a 34% yield. LC-MS (ESI): m / z 218.2 [M-56+H]. + .

[0434] Preparation of compound 61-3

[0435] Compound 61-2 (200 mg, 731.78 μmol) was dissolved in DCM (4 mL) at 0°C, and a solution of HCl in 1,4-dioxane (1 mL, 4 M) was slowly added dropwise. Stir for 2 hours. The supernatant was discarded and the mixture was dried to afford 100 mg of the target compound 61-3 in a 78% yield. This was used directly in the next reaction without purification.

[0436] Preparation of compound 61

[0437] Compound 7-1 (100 mg, 180.87 μmol) and acetonitrile (1 mL) were added to a reaction flask. Then, at room temperature, 61-3 (47 mg, 271.31 μmol) and DIPEA (1 mL) were added. The mixture was microwaved at 80°C for 2 hours. The reaction was monitored for completion by LCMS. The reaction solution was cooled to room temperature, water (30 mL) was added, and the mixture was extracted three times with EA (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate evaporated to dryness under reduced pressure. The crude product was purified by preparative liquid chromatography (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10% to 60% acetonitrile over 30 minutes; flow rate: 30 mL / min) to yield 50 mg of the title compound 61. LC-MS (ESI): m / z 689.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.33 (d, J=5.0Hz, 1H), 7.70 (d, J=2.4Hz, 1H), 7.63 (d, J=2. 4Hz, 1H), 7.59 (d, J=8.8Hz, 2H), 7.55 (d, J=8.5Hz, 2H), 7.30 (d, J=8.5Hz, 2H), 7.06 (d, J=8.8Hz, 2H), 6.74 (d, J=5.0Hz, 1H), 5.03 (s, 2H), 4.42 (t, J=5.6Hz, 2H), 4.09 ( s, 2H), 3.98-3.94 (m, 4H), 2.49-2.33 (m, 5H), 1.68 (s, 6H), 1.29 (d, J=12.8Hz, 6H). 31 P NMR (162MHz, DMSO-d6) δ41.04 (s, 1P).

[0438] Example 62: Preparation of Compound 62

[0439] Preparation of compound 62

[0440] Compound 15-2 (100 mg, 180.55 μmol) was dissolved in 1,4-dioxane (1 mL) and 19-1 (36.61 mg, 270.82 μmol), Pd2(dba)3 (16.53 mg, 18.05 μmol), DIEA (24 mg, 0.07 mmol), and Xantphos (20.89 mg, 36.11 μmol) were added sequentially. The atmosphere was purged with nitrogen three times and the mixture was stirred at 100°C for 2 hours. After the reaction, the insoluble solid was filtered off, the filtrate was added with water (10 mL), and extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. After purification by column chromatography (petroleum ether:ethyl acetate = 1:1), the crude product was obtained. The crude product was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 30 mg of the title compound 62. LC-MS (ESI): m / z 652.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.48 (d, J=5.1Hz, 1H), 8.44 (d, J=3.0Hz, 1H), 7.94 (d, J=8.1Hz, 2H), 7.8 9 (d, J=8.8Hz, 1H), 7.69 (d, J=2.4Hz, 1H), 7.62 (d, J=2.4Hz, 1H), 7.52 (dd, J=8.8, 3.0Hz, 1H), 7. 33 (d, J=8.1Hz, 2H), 7.03 (d, J=5.1Hz, 1H), 5.20 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 4.10-4.04 (m, 2H ), 3.95 (t, J=5.1Hz, 2H), 3.93-3.89 (m, 2H), 3.81-3.76 (m, 2H), 3.60-3.54 (m, 2H), 1.69 (s, 6H).

[0441] Example 63: Preparation of Compound 63

[0442] Preparation of compound 63-1

[0443] Compound (2-(methylthio)pyrimidin-4-yl)methanol (800 mg, 5.12 mmol) and 3,6-diiodopyridazine (1.7 g, 5.12 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). The reaction system was cooled to 0°C, and sodium hydroxide (410 mg, 10.24 mmol) was added portionwise. The reaction system was stirred at 25°C for 5 hours. After completion, the reaction system was quenched with saturated aqueous ammonium chloride (20 mL) and extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. Purification by column chromatography (EA / PE = 0-20%) afforded 550 mg of the title compound 63-1 in a yield of 29.8%. LC-MS (ESI): m / z 361.0 [M+H] + .

[0444] Preparation of compound 63-2

[0445] Compound 63-1 (200 mg, 0.555 mmol) was dissolved in 1,4-dioxane (10 mL) and water (3 mL). Compound 12-3 (255 mg, 0.555 mmol), potassium carbonate (230 mg, 1.67 mmol), and Pd(dppf)Cl2 (40 mg, 0.055 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the reaction system was stirred at 90°C for 5 hours. After completion of the reaction, water (30 mL) was added and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. Purification by column chromatography (EA / PE = 0-20%) afforded 200 mg of the title compound 63-2 in a 63% yield. LC-MS (ESI): m / z 566.2 [M+H] + .

[0446] Preparation of compound 63-3

[0447] Compound 63-2 (119 mg, 0.211 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperbenzoic acid (108 mg, 0.633 mmol) was added in batches at room temperature. The reaction system was stirred at room temperature for 2 hours. After completion of the reaction, the reaction system was quenched with saturated aqueous sodium sulfite solution (10 mL), extracted three times with dichloromethane (20 mL), and the organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. Purification by column chromatography (EA / PE = 0-60%) gave 80 mg of the title compound 63-3, in a yield of 63%. LC-MS (ESI): m / z 598.2 [M+H] + .

[0448] Preparation of compound 63

[0449] Compound 63-3 (35 mg, 0.035 mmol) was dissolved in acetonitrile (2 mL), and potassium carbonate (15 mg, 0.105 mmol) and dimethylphosphine oxide (8 mg, 0.105 mmol) were added sequentially. The reaction system was stirred at 80°C for 1 hour. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was concentrated to obtain the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 5 mg of the title compound 63. LC-MS (ESI): m / z 596.2 [M+H] + . 1H NMR (400MHz, Chloroform-d) δ8.86 (s, 1H), 7.95 (d, J=8.2Hz, 2H), 7.88 (d, J=9.1Hz, 1H), 7.54 (s, 1H), 7.46 (d, J=2.3Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.32 (d, J=8.2Hz, 2H), 7.24 (s, 1H), 5.81 (s, 2H), 4.43 (t, J=6.1Hz, 2H), 3.87 (t, J=6.1Hz, 2H), 1.88 (d, J=13.5Hz, 6H), 1.70 (s, 6H). 31 P NMR (162MHz, Chloroform-d) δ 35.44.

[0450] Example 64: Preparation of Compound 64

[0451] Preparation of compound 64

[0452] Compound 7-1 (100 mg, 180.87 μmol) and compound 64-1 (23.59 mg, 198.96 μmol) were weighed and dissolved in acetonitrile (2 mL). Triethylamine (54.91 mg, 542.62 μmol, 75.68 μL) was added. The reaction solution was purged with nitrogen three times. Microwave heating was performed at 80°C for 2 hours. LCMS analysis showed the disappearance of the starting material and the formation of the product. The reaction solution was purified by preparative purification to yield 60.5 mg of the title compound 64. LC-MS (ESI): m / z 598.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.41 (d, J=5.0Hz, 1H), 7.70 (d, J=2.4Hz, 1H), 7.64 (d, J=2.3Hz , 1H), 7.60 (d, J=8.8Hz, 2H), 7.56 (d, J=8.4Hz, 2H), 7.30 (d, J=8.4Hz, 2H), 7.08 (d, J=8. 8Hz, 2H), 6.87 (d, J=5.0Hz, 1H), 5.08 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 4.34 (t, J=8.8Hz, 2 H), 4.19 (dd, J=8.6, 5.8Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 3.90-3.85 (m, 1H), 1.68 (s, 6H).

[0453] Example 65: Preparation of Compound 65

[0454] Preparation of compound 65-1

[0455] Compound 48-2 (200 mg, 0.39 mmol) was dissolved in methanol (10 mL), and 2-chloro-4-bromopyrimidine (90 mg, 0.47 mmol) and triethylamine (79 mg, 0.78 mmol) were added sequentially. The reaction system was stirred at 25°C for 1 hour. After the reaction, water (10 mL) was added and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by column chromatography (PE:EA = 60%) to obtain 200 mg of the title compound 65-1. LC-MS (ESI): m / z 621.2 [M+H] + .

[0456] Preparation of compound 65

[0457] Compound 65-1 (100 mg, 0.16 mmol) was dissolved in DMF (5 mL), and 1-imino-1-oxothiolane (57 mg, 0.48 mmol), DIPEA (62 mg, 0.48 mmol), tris(dibenzylidene-BASE acetone)dipalladium (18 mg, 0.02 mmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (27 mg, 0.05 mmol) were added sequentially. The reaction system was stirred at 80°C for 16 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was then purified by preparative separation (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 40% to 60% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 23.6 mg of the title compound 65. LC-MS (ESI): m / z 704.3 [M+H] + . 1H NMR (400MHz, Chloroform-d) δ8.04 (d, J=6.6Hz, 1H), 7.54-7.45 (m, 5H), 7.37 (d, J=2 .3Hz, 1H), 7.22 (d, J=8.4Hz, 2H), 6.99 (d, J=8.7Hz, 2H), 6.20 (d, J=6.6Hz, 1H), 4.68 -4.63 (m, 1H), 4.43 (t, J = 6.2Hz, 2H), 3.94-3.84 (m, 2H), 3.88 (t, J = 6.2Hz, 2H), 3.83 -3.66(m, 4H), 3.42-3.30(m, 2H), 2.37-2.22(m, 4H), 2.04-1.89(m, 4H), 1.69(s, 6H).

[0458] Example 66 and Example 67: Preparation of Compounds 66 and 67

[0459] Preparation of compound 66-3

[0460] Under nitrogen at 0°C, compound 66-1 (0.5 g, 2.20 mmol) and compound 66-2 (0.5 g, 2.20 mmol) were dissolved in DCM (10 mL). A solution of HCl in 1,4-dioxane (5 mL, 4 M) was slowly added dropwise. The mixture was stirred at 0°C for 2 hours. The supernatant was discarded and the mixture was dried to give 560 mg of crude title compound 66-3, which was used directly in the next reaction.

[0461] Preparation of compound 66-4

[0462] Compound 66-3 (705.98 mg, 4.40 mmol), 4-chloro-2-(methylthio)pyrimidine (560 mg, 4.40 mmol), triethylamine (4.45 g, 43.95 mmol, 6.13 mL), and acetonitrile (10 mL) were added to a reaction flask and stirred at 80°C for 16 hours. The reaction mixture was dried by rotary evaporation, and the crude product was purified by column chromatography using 100% EA / PE to obtain 800 mg of the title compound 66-4 in a 72% yield. LC-MS (ESI): m / z 252.2.

[0463] Preparation of compound 66-5

[0464] 4-Iodophenol (500 mg, 2.27 mmol), compound 66-4 (571 mg, 2.27 mmol), CMBP (cyanomethylenetri-n-butylphosphine, 1.1 g, 4.55 mmol), and toluene (5 mL) were added to a reaction flask and stirred at 110°C under nitrogen for 2 hours. The reaction mixture was dried and the crude product was purified by column chromatography (EA / PE = 50%) to obtain 900 mg of the title compound 66-5 in an 87% yield. LC-MS (ESI): m / z 454.0.

[0465] Preparation of compound 66-6

[0466] Under atmospheric pressure, compound 66-5 (500 mg, 1.10 mmol), compound 12-3 (507.57 mg, 1.10 mmol), KCO (457.29 mg, 3.31 mmol), Pd(dppf)Cl (161.40 mg, 220.59 μmol), 1,4-dioxane (5 mL), and water (1 mL) were added to a reaction flask and stirred at 100°C for 16 hours. The mixture was then spin-dried and the crude product was purified by column chromatography (EA / PE = 100%) to afford 350 mg of the title compound 66-6 in a 48% yield. LC-MS (ESI): m / z 659.5.

[0467] Preparation of compound 66-7

[0468] Compound 66-6 (350 mg, 530.57 μmol) was dissolved in DCM (3 mL). Under nitrogen, m-CPBA (274.7 mg, 1.59 mmol) was added portionwise at 0°C and allowed to react at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium thiosulfate (5 mL) and extracted three times with DCM (5 mL). The organic phases were combined, washed three times with saturated aqueous sodium carbonate (5 mL), dried over anhydrous sodium sulfate, and spin-dried to afford 300 mg of crude title compound 66-7 in an 81% yield. LC-MS (ESI): m / z 691.3.

[0469] Preparation of Compound 66 and Compound 67

[0470] Compound 66-7 (300 mg, 433.74 μmol), Cs2CO3 (424 mg, 1.30 mmol), dimethylphosphine oxide (80.74 mg, 1.30 mmol), and acetonitrile (3 mL) were added to a reaction flask and stirred at 80°C for 2 hours. The mixture was filtered and dried, and the resulting crude product was purified by preparative liquid chromatography (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-70% acetonitrile over 30 minutes; flow rate: 30 mL / min) to obtain 20 mg of the title compound 66 and 20 mg of the title compound 67.

[0471] Compound 66: HPLC analysis method (chromatographic column: Agilent ZORBAX Extend-C18 4.6*150 mm, 3.5 μm; column temperature: 30°C; mobile phase: water (0.1 mL / 1 L trifluoroacetic acid)-acetonitrile (0.4 mL / 4 L trifluoroacetic acid); acetonitrile content of the mobile phase was gradually increased from 5% to 95% over 8 minutes and maintained at 95% acetonitrile for 7 minutes; flow rate: 1 mL / min), retention time RT = 8.194 min. LC-MS (ESI): m / z 689.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.33 (d, J=6.1Hz, 1H), 7.70 (d, J=2.3Hz, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.54 (d, J=8.8Hz, 2H), 7.53 (d, J=8.3Hz, 2H), 7.29 (d, J=8.3Hz, 2H), 7.04 (d , J=8.8Hz, 2H), 6.88 (dd, J=6.2, 3.2Hz, 1H), 5.09-4.96 (m, 1H), 4.92 (brs, 1H), 4.55 (brs, 1H), 4.42 (t, J = 5.2Hz, 2H), 3.95 (t, J = 5.2Hz, 2H), 2.24-2.13 (m, 2H), 2.02 (brs 4H), 1.68 (d, J=13.5Hz, 6H), 1.67 (s, 6H), 1.62-1.46 (m, 2H). 31 P NMR (162MHz, DMSO-d6) δ33.95 (s, 1P).

[0472] Compound 67: HPLC analysis (column: Agilent ZORBAX Extend-C18 4.6*150 mm, 3.5 μm; column temperature: 30°C; mobile phase: water (containing 0.1 mL / 1 L trifluoroacetic acid)-acetonitrile (containing 0.4 mL / 4 L trifluoroacetic acid); mobile phase: acetonitrile content increased from 5% to 95% over 8 minutes and maintained at 95% acetonitrile for 7 minutes; flow rate: 1 mL / min), retention time RT = 8.522 min. LC-MS (ESI): m / z 689.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.30 (d, J=6.2Hz, 1H), 7.70 (d, J=2.3Hz, 1H), 7.64 (d, J=2.3Hz, 1H), 7.59 (d, J= 8.6Hz, 2H), 7.55 (d, J=8.4Hz, 2H), 7.30 (d, J=8.4Hz, 2H), 6.98 (d, J=8.6Hz, 2H), 6.84 (dd, J=6.2, 3.2Hz, 1H), 4.83 (brs, 1H), 4.70 (t, J=4.9Hz, 1H), 4.50 (brs, 1H), 4.42 (t, J=5.2Hz, 2H), 3.95 (t, J=5.2Hz, 2H) , 2.23 (d, J=7.1Hz, 2H), 2.10-1.97 (m, 4H), 1.94 (d, J=14.8Hz, 2H), 1.68 (s, 6H), 1.67 (d, J=13.6Hz, 6H). 31 P NMR (162MHz, DMSO-d6) δ33.67 (s, 1P).

[0473] Example 68: Preparation of Compound 68

[0474] Preparation of compound 68-2

[0475] Under nitrogen, compound 68-1 (100 mg, 691.76 μmol), dimethylphosphine oxide (80.99 mg, 1.04 mmol), DIEA (268 mg, 2.08 mmol, 361.48 μL), Xtantphos (80.05 mg, 138.35 μmol), Pd2(dba)3 (63.35 mg, 69.18 μmol), and DMF (2 mL) were added to a microwave tube and stirred at 140°C for 2 hours. The mixture was filtered, the filtrate was dried, and the crude product was purified by column chromatography (MeOH / DCM = 0-20%) to obtain 100 mg of the title compound 68-2 in a 77% yield. LC-MS (ESI): m / z 187.2.

[0476] Preparation of compound 68-3

[0477] Under nitrogen, compound 68-2 (500 mg, 2.69 mmol) and triethylamine (543.6 mg, 5.37 mmol, 749.28 μL) were dissolved in DCM (11 mL). Methanesulfonyl chloride (369.23 mg, 3.22 mmol) was added dropwise at 0°C and stirred for 2 hours. After completion of the reaction, water (10 mL) was added to quench the reaction and the mixture was extracted three times with DCM (10 mL). The organic phases were combined, dried, and purified by column chromatography (EA / PE = 0-15%) to afford 660 mg of the title compound 68-3 in a 92% yield. LC-MS (ESI): m / z 265.0.

[0478] Preparation of compound 68-4

[0479] Compound 5-bromoindole (323.48 mg, 1.22 mmol) and DMF (4 mL) were added to a reaction flask. NaH (53.04 mg, 1.33 mmol, 60% purity) was added at 0°C. After stirring for 20 minutes, a solution of compound 68-3 (200 mg, 1.02 mmol) in DMF (1 mL) was added dropwise. The mixture was stirred at 0°C for 2 hours. The reaction was quenched with water (10 mL) and extracted three times with DCM (10 mL). The organic phases were combined and dried. The crude product was purified by column chromatography (MeOH / DCM = 0-5%) to obtain 90 mg of the title compound 68-4 in a 24% yield. LC-MS (ESI): m / z 364.0.

[0480] Preparation of compound 68

[0481] Under nitrogen protection, compound 12-3 (101 mg, 219.67 μmol), compound 68-4 (80 mg, 219.67 μmol), K2CO3 (91.1 mg, 659.02 μmol), Pd(dppf)Cl2 (32 mg, 43.93 μmol), 1,4-dioxane (0.5 mL) and H2O (0.2 mL) were added to the reaction flask and stirred at 100 °C for 16 hours. The crude product was filtered and dried, and purified by preparative liquid chromatography (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 5%-75% acetonitrile over 30 minutes; flow rate: 30 mL / min) to give 20 mg of the title compound 68. LC-MS (ESI): m / z 617.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.84 (d, J=5.2Hz, 1H), 7.85 (d, J=1.7Hz, 1H), 7.72 (d, J=2.4Hz, 1H), 7. 65 (d, J=2.3Hz, 1H), 7.60 (d, J=8.1Hz, 2H), 7.56 (d, J=3.1Hz, 1H), 7.49 (d, J=8.6Hz, 1H), 7.41 (d d, J=8.6, 1.7Hz, 1H), 7.31 (d, J=8.1Hz, 2H), 6.96 (dd, J=5.2, 3.1Hz, 1H), 6.61 (d, J=3.1Hz, 1H), 5.67 (s, 2H), 4.42 (t, J = 5.2Hz, 2H), 3.96 (t, J = 5.2Hz, 2H), 1.72 (d, J = 13.7Hz, 6H), 1.69 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.20 (s, 1P).

[0482] Example 69: Preparation of Compound 69

[0483] Preparation of compound 69-1

[0484] Compound 12-3 (500 mg, 1.09 mmol) was dissolved in a solution of 1,4-dioxane (5.0 mL) and water (2.0 mL). [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (199 mg, 0.21 mmol), 5-bromo-2-methoxythiazole (317 mg, 1.63 mmol), and potassium carbonate (300 mg, 2.18 mmol) were added sequentially. The reaction system was stirred at 100°C for 2 hours. After completion of the reaction, the filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by column chromatography (EA / PE = 0-30%) afforded 300 mg of the title compound 69-1. LC-MS (ESI): m / z 447.2 [M+H] + .

[0485] Preparation of compound 69-2

[0486] Compound 69-1 (300 mg, 0.67 mmol) was dissolved in 1,4-dioxane (3 mL) and the reaction mixture was cooled to 0°C. Dioxane hydrochloride (4 mol / L, 1.7 mL, 6.70 mmol) was added. The reaction system was stirred at room temperature for 2 hours. After the reaction, the filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Purification by column chromatography (EA / PE = 0-50%) gave 100 mg of the title compound 69-2. LC-MS (ESI): m / z 433.0 [M+H] + .

[0487] Preparation of compound 69

[0488] Compound 69-2 (100 mg, 0.23 mmol) was dissolved in acetonitrile (5 mL), followed by the addition of 68-3 (73 mg, 0.28 mmol) and cesium carbonate (150 mg, 0.46 mmol). The reaction system was stirred at 80°C for 2 hours. After completion of the reaction, the filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Preparative separation and purification (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 3 mg of the title compound 69. LC-MS (ESI): m / z 601.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.95 (d, J=5.3Hz, 1H), 7.68 (s, 1H), 7.67 (d, J=2.3Hz, 1H), 7.60 (d, J=2.3Hz, 1H), 7.53 (dd, J=5.3, 3.2Hz, 1H), 7.3 7 (d, J=8.6Hz, 2H), 7.29 (d, J=8.6Hz, 2H), 5.17 (s, 2H), 4.41 (t, J=5.2Hz, 2H), 3.95 (t, J=5.2Hz, 2H), 1.70 (d, J=13.7Hz, 6H), 1.65 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.31 (s, 1P).

[0489] Example 70: Preparation of Compound 70

[0490] Preparation of compound 70-2

[0491] Compound 1-8 (500 mg, 1.17 mmol) and compound 70-1 (241.55 mg, 1.29 mmol) were weighed into a 30 mL microwave tube, and CMBP (566 mg, 2.35 mmol) and toluene (10 mL) were added. The atmosphere was replaced with nitrogen three times. The reaction mixture was heated at 100°C for 2 hours. LCMS showed the disappearance of the starting material and the formation of the product. The reaction mixture was spin-dried and purified by column chromatography (EtOAc / PE = 0-5%) to obtain 600 mg of the title compound 70-2 in an 85.9% yield. LC-MS (ESI): m / z 539.2 [M-56+H] + .

[0492] Preparation of compound 70-3

[0493] At 0°C, compound 70-2 (600 mg, 1.01 mmol) was weighed and dissolved in DCM (5 mL). A solution of hydrogen chloride in 1,4-dioxane (4 M, 10.07 mmol, 2.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 h. LCMS showed that the starting material disappeared and product was generated. The reaction mixture was poured into a saturated Na2CO3 solution (50 mL). The organic phase was extracted three times with DCM (30 mL*3), washed three times with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and dried under reduced pressure to obtain 400 mg of the title compound 70-3, with a yield of 80.1%. The product was used directly in the next step without purification. LC-MS (ESI): m / z 495.2 [M+H] + .

[0494] Preparation of compound 70-4

[0495] Compound 70-3 (400 mg, 807.36 μmol) and 4-chloro-2-(methylsulfonyl)pyrimidine (233.3 mg, 1.21 mmol) were dissolved in DCM (10 mL), and DIPEA (208.7 mg, 1.61 mmol, 281.26 μL) was added. The reaction mixture was stirred at 0°C for 2 hours. LCMS showed the disappearance of the starting material and the formation of the product. The reaction mixture was dried and purified by column chromatography (EtOAc / PE = 0-50%) to give 300 mg of the title compound 70-4 in a 57% yield. LC-MS (ESI): m / z 651.2 [M+H] + .

[0496] Preparation of compound 70

[0497] Compound 70-4 (300 mg, 460.40 μmol) and dimethylphosphine oxide (359.4 mg, 4.60 mmol) were dissolved in CH3CN (8 mL), and Cs2CO3 (450 mg, 1.38 mmol) was added. The reaction mixture was stirred at 80°C for 2 hours. LCMS showed the disappearance of the starting material and the formation of the product. The reaction mixture was filtered, and the filtrate was poured into water (20 mL) and extracted three times with ethyl acetate (25 mL). The organic phases were combined, washed with water, then three times with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and spun down. The resulting residue was purified by preparative purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 55%-75% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 58 mg of the title compound 70. LC-MS (ESI): m / z 649.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.27 (dd, J=6.0, 1.0Hz, 1H), 7.70 (d, J=2.3Hz, 1H), 7.64 (d, J=2.3Hz, 1H), 7.59 (d, J= 8.8Hz, 2H), 7.56 (d, J=8.5Hz, 2H), 7.30 (d, J=8.5Hz, 2H), 7.04 (d, J=8.8Hz, 2H), 6.50 (dd, J=6.0, 3.2Hz, 1H), 4.42 (t, J=5.3H z, 2H), 4.29-4.19 (m, 4H), 3.95 (t, J=5.3Hz, 2H), 3.94-3.90 (m, 2H), 3.28-3.17 (m, 1H), 1.68 (s, 6H), 1.65 (d, J=13.5Hz, 6H). 31 P NMR (162MHz, DMSO-d6) δ33.36 (s, 1P).

[0498] Example 71: Preparation of Compound 71

[0499] Preparation of compound 71-2

[0500] Compound 71-1 (100 mg, 0.67 mmol) was dissolved in dichloromethane (2 mL), and 4-methylbenzenesulfonyl chloride (140 mg, 0.74 mmol) and DMAP (8.2 mg, 0.07 mmol) were added sequentially. The temperature was lowered to 0°C, and triethylamine (203 mg, 2.01 mmol) was added dropwise. The reaction system was stirred at 25°C for 4 hours. After the reaction was completed, water (10 mL) was added and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by column chromatography (EA / PE = 0-30%) to obtain 120 mg of the title compound 71-2.

[0501] Preparation of compound 71

[0502] Compound 71-2 (100 mg, 0.23 mmol) was dissolved in DMF (2 mL), followed by the addition of 1-8 (79 mg, 0.26 mmol) and cesium carbonate (153 mg, 0.47 mmol). The reaction system was stirred at 90°C for 4 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 11 mg of the title compound 71. LC-MS (ESI): m / z 558.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.81-7.69 (m, 2H), 7.65-7.55 (m, 4H), 7.31 (dd, J=9.1, 2.7Hz, 2H), 7.11 (d, J=8.8Hz, 2H), 4.80-4 .73 (m, 1H), 4.48-4.37 (m, 2H), 4.01-3.92 (m, 2H), 3.24-3.17 (m, 4H), 2.22 (dt, J=14.1, 8.0Hz, 4H), 1.69 (d, J=6.7Hz, 6H).

[0503] Example 72: Preparation of Compound 72

[0504] Preparation of compound 72

[0505] Compound 49-2 (100 mg, 0.23 mmol) was dissolved in dichloromethane (3 mL), and oxetane-3-carboxaldehyde (86 mg, 0.93 mmol) and triethylamine (118 mg, 1.16 mmol) were added in sequence. The reaction system was stirred at 25° C. for 0.5 hour. Sodium acetate borohydride (246 mg, 1.16 mmol) was added, and stirring was continued for 3 hours. After the reaction, water (10 mL) was added and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 41 mg of the title compound 72. LC-MS (ESI): m / z 500.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.44 (d, J=2.3Hz, 1H), 7.26 (d, J=2.3Hz, 1H), 7.02 (d, J=8.6Hz, 2H), 6.39 (d, J=8.6Hz, 2H), 4. 84 (t, J=6.9Hz, 2H), 4.46-4.37 (m, 4H), 4.11 (brs, 4H), 4.03 (s, 4H), 3.87 (t, J=6.2Hz, 2H), 3.38-3.21 (m, 3H), 1.61 (s, 6H).

[0506] Example 73: Preparation of Compound 73

[0507] Preparation of compound 73-1

[0508] Dissolve 4-hydroxypyran (200 mg, 1.96 mmol) in dichloromethane (2 mL), and add p-toluenesulfonyl chloride (411 mg, 2.15 mmol) and 4-dimethylaminopyridine (24 mg, 0.20 mmol) sequentially. Cool to 0°C, and add triethylamine (595 mg, 5.87 mmol) dropwise. The reaction system is stirred at 25°C for 12 hours. After the reaction is complete, add water (10 mL) and extract three times with dichloromethane (20 mL). The organic phases are combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate is concentrated to obtain the crude product, which is purified by column chromatography (PE:EA = 30%) to obtain 380 mg of the title compound 73-1.

[0509] Preparation of compound 73

[0510] Compound 1-8 (150 mg, 0.35 mmol) was dissolved in dimethyl sulfoxide (2.0 mL), and compound 73-1 (99 mg, 0.39 mmol) and cesium carbonate (230 mg, 0.70 mmol) were added sequentially. The reaction system was stirred at 60°C for 12 hours. The reaction solution was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 41 mg of the title compound 73. LC-MS (ESI): m / z 510.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.54-7.49 (m, 3H), 7.49-7.46 (m, 2H), 7.40 (dd, J=20.6, 2.3Hz, 1H), 7.22 (dd, J=8.3, 3.4Hz, 2H), 6.99 (d, J=8. 7Hz, 2H), 4.53 (m, 1H), 4.42 (t, J=6.2Hz, 2H), 4.01 (m, 2H), 3.88 (t, J=6.2Hz, 2H), 3.60 (m, 2H), 2.12-2.01 (m, 2H), 1.82 (m, 2H), 1.70 (s, 6H).

[0511] Example 74: Preparation of Compound 74

[0512] Preparation of Compound 74

[0513] Compound 1-8 (100 mg, 0.23 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and (tetrahydro-2H-pyran-4-yl)methanol (30 mg, 0.26 mmol) and triphenylphosphine (123 mg, 0.47 mmol) were added sequentially. The atmosphere was replaced with nitrogen three times, and the temperature was lowered to 0°C. Diisopropyl azodicarboxylate (95 mg, 0.47 mmol) was added dropwise. The reaction system was stirred at 25°C for 12 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) afforded 2 mg of the title compound 74. LC-MS (ESI): m / z 524.3 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.53-7.46 (m, 5H), 7.38 (d, J=2.3Hz, 1H), 7.22 ( d, J=8.4Hz, 2H), 6.96 (d, J=8.8Hz, 2H), 4.42 (t, J=6.2Hz, 2H), 4.03 (dd, J=11.2 , 3.4Hz, 2H), 3.88 (t, J=6.2Hz, 2H), 3.85 (d, J=6.5Hz, 2H), 3.46 (td, J=11.9, 2. 0Hz, 2H), 2.14-2.04 (m, 1H), 1.78 (d, J=12.9Hz, 2H), 1.69 (s, 6H), 1.49 (m, 2H).

[0514] Example 75: Preparation of Compound 75

[0515] Preparation of compound 75-2

[0516] Compound 75-1 (130 mg, 1.14 mmol) was dissolved in dichloromethane (2 mL), and p-toluenesulfonyl chloride (191 mg, 1.14 mmol) and 4-dimethylaminopyridine (14 mg, 0.11 mmol) were added sequentially. The temperature was lowered to 0°C, and triethylamine (345 mg, 3.41 mmol) was added dropwise. The reaction system was stirred at 25°C for 12 hours. After the reaction, water (10 mL) was added and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. Purification by column chromatography (EA / PE = 0-30%) afforded 235 mg of the title compound 75-2. LC-MS (ESI): m / z 286.2 [M+H2O] + .

[0517] Preparation of compound 75

[0518] Compound 1-8 (100 mg, 0.23 mmol) was dissolved in dimethyl sulfoxide (2 mL), followed by the addition of compound 75-2 (69 mg, 0.26 mmol) and cesium carbonate (153 mg, 0.47 mmol). The reaction system was stirred at 60°C for 12 hours. The reaction solution was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 8 mg of the title compound 4. LC-MS (ESI): m / z 544.2 [M+Na] + . 1 H NMR (400MHz, Chloroform-d) δ7.52-7.44 (m, 5H), 7.37 (d, J=2.3Hz, 1H), 7.22 (d, J=8.5Hz, 2H), 6.84 (d, J=8.7Hz, 2H), 4.77 (s, 2H) , 4.71 (s, 2H), 4.59-4.52 (m, 1H), 4.43 (t, J=6.2Hz, 2H), 3.88 (t, J=6.2Hz, 2H), 2.90-2.79 (m, 2H), 2.43-2.35 (m, 2H), 1.69 (s, 6H).

[0519] Example 76: Preparation of Compound 76

[0520] Preparation of compound 76-1

[0521] Compound 56-1 (250 mg, 553.90 μmol) and 2-chloro-4-(chloromethyl)pyrimidine (99.3 mg, 609.29 μmol) were dissolved in CH3CN (5 mL), and K2CO3 (229.7 mg, 1.66 mmol) was added. The reaction mixture was stirred at 85°C for 2 hours. LCMS showed the disappearance of the starting material and the formation of the product. The reaction mixture was used directly in the next step without post-treatment or purification. LC-MS (ESI): m / z 577.2 [M+H] + .

[0522] Preparation of Compound 76

[0523] Compound 53-1 (114.1 mg, 664.49 μmol) and triethylamine (112.1 mg, 1.11 mmol, 154.47 μL) were added to the above reaction mixture. The reaction mixture was stirred at 80°C for 12 hours. LCMS showed the disappearance of the starting material and the formation of the product. The reaction mixture was filtered and purified using preparative purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-75% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 96.7 mg of the title compound 76. LC-MS (ESI): m / z 676.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.31 (d, J=5.4Hz, 1H), 8.25 (d, J=1.9Hz, 1H), 7.75-7.70 ( m, 2H), 7.65 (d, J=8.6Hz, 2H), 7.65 (d, J=2.3Hz, 1H), 7.57 (d, J=8.6Hz, 1H), 7.38 ( d, J=8.6Hz, 2H), 6.85 (d, J=5.3Hz, 1H), 6.51 (s, 2H), 4.44-4.37 (m, 3H), 4.43 (t, J =5.2Hz, 2H), 4.34-4.26 (m, 2H), 3.96 (t, J=5.2Hz, 2H), 3.10 (s, 3H), 1.71 (s, 6H).

[0524] Example 77: Preparation of Compound 77

[0525] Preparation of compound 77

[0526] Compound 48-3 (100 mg, 0.15 mmol) was dissolved in acetonitrile (5 mL), and 2-oxa-6-azaspiro[3,3]heptane (45 mg, 0.45 mmol) and potassium carbonate (62 mg, 0.45 mmol) were added sequentially. The reaction system was stirred at 80°C for 16 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 45% to 65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 34.3 mg of the title compound 77. LC-MS (ESI): m / z 684.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.90 (d, J=6.4Hz, 1H), 7.52 (d, J=8.8Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 7.49 (d, J=2.4Hz, 1H), 7.37 (d, J=2.4Hz, 1H), 7.23 (d, J=8.4Hz, 2H), 7.00 (d, J=8.8Hz, 2H), 5.99 (d , J=6.5Hz, 1H), 4.83 (s, 4H), 4.68-4.58 (m, 1H), 4.43 (t, J=6.2Hz, 2H), 4.28 (s, 4H), 3.88 (t, J=6.2 Hz, 2H), 3.87-3.82 (m, 2H), 3.70-3.59 (m, 2H), 2.05-1.94 (m, 2H), 1.94-1.86 (m, 2H), 1.70 (s, 6H).

[0527] Example 78: Preparation of Compound 78

[0528] Preparation of Compound 78

[0529] Compound 48-3 (100 mg, 0.15 mmol) was dissolved in acetonitrile (5 mL), and 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide hydrochloride (66 mg, 0.45 mmol) and potassium carbonate (62 mg, 0.45 mmol) were added in sequence. The reaction system was stirred at 80°C for 16 hours. After the reaction, the insoluble solids were filtered off, and the filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 27.2 mg of the title compound 78. LC-MS (ESI): m / z 732.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.93 (d, J=6.3Hz, 1H), 7.52 (d, J=8.8Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 7.49 (d, J=2.4Hz, 1H), 7.37 (d, J=2.3Hz, 1H), 7.23 (d, J=8.4Hz, 2H), 7.00 (d, J=8.8Hz, 2H), 6.03 (d , J=6.3Hz, 1H), 4.66-4.57 (m, 1H), 4.43 (t, J=6.2Hz, 2H), 4.35 (s, 4H), 4.31 (s, 4H), 3.88 (t, J=6.2 Hz, 2H), 3.87-3.80 (m, 2H), 3.68-3.57 (m, 2H), 2.04-1.93 (m, 2H), 1.93-1.81 (m, 2H), 1.70 (s, 6H).

[0530] Example 79: Preparation of Compound 79

[0531] Preparation of compound 79

[0532] Compound 21-4 (30 mg, 54.86 μmol) was dissolved in N,N-dimethylformamide (0.5 mL), and dimethylphosphine oxide (6.4 mg, 82.29 μmol), N,N-diisopropylethylamine (14.2 mg, 109.71 μmol), tris(dibenzylideneacetone)dipalladium (2 mg, 2.74 μmol), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (1.6 mg, 2.74 μmol) were added in sequence. The atmosphere was purged with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After completion of the reaction, the reaction system was filtered, the filtrate was added with water (20 mL), and extracted three times with dichloromethane (20 mL). The organic phases were combined, dried, and concentrated to obtain the crude product, which was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 10% to 45% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 4.4 mg of the title compound 79. LC-MS (ESI): m / z 588.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.19 (s, 2H), 7.81 (d, J = 8.4Hz, 2H), 7.72 (d, J = 8.4Hz, 2H), 7.72 (d, J = 2.3Hz, 1H), 7.70 (d, J = 8.4Hz, 2H), 7.65 (d, J=2.3Hz, 1H), 7.38 (d, J=8.4Hz, 2H), 4.43 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 1.79 (d, J=13.8Hz, 6H), 1.70 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.43.

[0533] Example 80: Preparation of Compound 80

[0534] Preparation of Compound 80-2

[0535] Compound 80-1 (250 mg, 2.15 mmol) was dissolved in dichloromethane (12 mL). Triethylamine (653.4 mg, 6.46 mmol, 0.9 mL) and DMAP (52.6 mg, 430.45 μmol) were added separately at room temperature. p-Toluenesulfonyl chloride (902.70 mg, 4.73 mmol) was slowly added, and the mixture was stirred at room temperature overnight. After the reaction was complete, dilution was added to the reaction mixture with dichloromethane, silica gel was added, and the mixture was concentrated. Purification was performed using an automated column chromatography (EA / PE = 0-30%) to obtain 683 mg of the title compound 80-2 in a 74.8% yield. LC-MS (ESI): m / z 442.2 [M+18]. + .1HNMR (400MHz, Chloroform-d) δ7.80-7.74 (m, 4H), 7.38-7.32 (m, 4H), 3.98 (d, J=6.6Hz, 2H), 3.88 (d, J= 6.2Hz, 2H), 2.59-2.47 (m, 2H), 2.45 (s, 6H), 2.09-2.01 (m, 1H), 1.83 (t, J=7.5Hz, 2H), 1.53-1.42 (m, 1H).

[0536] Preparation of compound 80-3

[0537] Compound 1-8 (60 mg, 140.73 μmol) was dissolved in DMF (1.5 mL), and compound 80-2 (65.7 mg, 154.81 μmol) and cesium carbonate (68.8 mg, 211.10 μmol) were added. The reaction mixture was stirred at 60°C overnight. After the reaction was completed, it was cooled to room temperature, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified using an automated column chromatography (EA / PE = 0-25%) to obtain 75.7 mg of the title compound 80-3 in a yield of 79.3%. LC-MS (ESI): m / z 695.3 [M+18]. + .

[0538] Preparation of Compound 80

[0539] Compound 80-3 (75.7 mg, 111.54 μmol) was dissolved in acetonitrile (1.5 mL), and 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide hydrochloride (22.5 mg, 122.70 μmol) and DIPEA (43.3 mg, 334.63 μmol, 58.3 μL) were added. The reaction mixture was stirred overnight at 90°C in a sealed tube. After completion of the reaction, the mixture was cooled to room temperature, diluted with a small amount of acetonitrile, and purified by preparative chromatography (preparative method: mobile phase: A: 10 mM aqueous ammonium bicarbonate; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: B%: 80%-90% over 8 min, 95% over 6 min; flow rate: 30 mL / min) to afford 2 mg of the title compound 80. LC-MS (ESI): m / z 653.4 [M+H] + .

[0540] Example 81: Preparation of Compound 81

[0541] Preparation of Compound 81

[0542] Compound 1-9 (30 mg, 53.14 μmol) and DCM (3 mL) were added to a reaction flask, followed by the addition of mCPBA (11.33 mg, 55.80 μmol, 85% purity) and stirring at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium thiosulfate (3 mL) and extracted three times with DCM (3 mL). The organic phases were combined and dried, and the crude product was purified by preparative liquid chromatography (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-80% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 20 mg of the title compound 81. LC-MS (ESI): m / z 580.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.01 (d, J=4.8Hz, 1H), 7.96-7.43 (m, 7H), 7.30 (d, J=7.9Hz, 2H), 7.14 (d, J=8.2Hz, 2H), 5.37 (s, 2H), 4.42 (s, 2H), 3.96 (s, 2H), 2.89 (s, 3H), 1.68 (s, 6H).

[0543] Example 82: Preparation of Compound 82

[0544] Preparation of compound 82

[0545] 2-Oxa-6-azaspiro[3.3]heptane (21.5 mg, 216.66 μmol), compound 15-2 (80 mg, 144.44 μmol), DIPEA (186.7 mg, 1.44 mmol, 251.6 μL), and acetonitrile (1 mL) were added to a reaction flask and stirred in a microwave oven at 80°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and dried by spin drying. The crude product was purified by preparative liquid chromatography (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-80% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 50 mg of the title compound 82. LC-MS (ESI): m / z 616.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.43 (d, J=3.0Hz, 1H), 8.37 (d, J=5.0Hz, 1H), 7.94 (d, J=8. 5Hz, 2H), 7.89 (d, J=8.8Hz, 1H), 7.70 (d, J=2.3Hz, 1H), 7.62 (d, J=2.3Hz, 1H), 7.52 ( dd, J=8.8, 3.0Hz, 1H), 7.33 (d, J=8.6Hz, 2H), 6.80 (d, J=5.0Hz, 1H), 5.13 (s, 2H), 4 .72 (s, 4H), 4.42 (t, J=5.2Hz, 2H), 4.20 (s, 4H), 3.96 (t, J=5.2Hz, 2H), 1.69 (s, 6H).

[0546] Example 83: Preparation of Compound 83

[0547] Preparation of compound 83

[0548] Compound 15-2 (100 mg, 180.55 μmol), compound 61-3 (46.9 mg, 270.82 μmol), DIPEA (233 mg, 1.81 mmol, 314.48 μL), and acetonitrile (717 μL) were added to a reaction vial and stirred in a microwave-assisted reaction at 80°C for 2 hours. The mixture was then dried and the crude product was purified by preparative liquid chromatography (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 10%-80% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 50 mg of the title compound 83. LC-MS (ESI): m / z 690.6 [M+H]+ . 1 H NMR (400MHz, DMSO-d6) δ8.43 (d, J=3.0Hz, 1H), 8.35 (d, J=5.0Hz, 1H), 7.95 (d, J=8.6Hz, 2H), 7. 89 (d, J=8.8Hz, 1H), 7.70 (d, J=2.4Hz, 1H), 7.62 (d, J=2.3Hz, 1H), 7.52 (dd, J=8.9, 3.0Hz, 1H), 7.33 (d, J=8.6Hz, 2H), 6.78 (d, J=5.0Hz, 1H), 5.13 (s, 2H), 4.42 (t, J=5.6Hz, 2H), 4.08 (s, 2H), 3.99-3.91(m, 4H), 2.49-2.41(m, 1H), 2.40-2.30(m, 4H), 1.69(s, 6H), 1.28(d, J=12.7Hz, 6H). 31 P NMR (162MHz, DMSO-d6) δ40.72 (s, 1P).

[0549] Example 84: Preparation of Compound 84

[0550] Preparation of compound 84

[0551] Compound 15-2 (76 mg, 138.44 μmol), 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide (30.6 mg, 207.65 μmol), DIPEA (178.9 mg, 1.38 mmol, 241 μL), and acetonitrile (790 μL) were added to a reaction vial and stirred in a microwave oven at 80°C for 2 hours. The mixture was then dried and the crude product was purified by preparative liquid chromatography (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-80% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 50 mg of the title compound 84. LC-MS (ESI): m / z 664.4 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.44 (d, J=3.0Hz, 1H), 8.40 (d, J=5.0Hz, 1H), 7.95 (d, J=8. 2Hz, 2H), 7.89 (d, J=8.8Hz, 1H), 7.69 (d, J=2.4Hz, 1H), 7.62 (d, J=2.3Hz, 1H), 7.52 ( dd, J=8.8, 3.1Hz, 1H), 7.33 (d, J=8.1Hz, 2H), 6.86 (d, J=5.0Hz, 1H), 5.15 (s, 2H), 4 .51 (s, 4H), 4.42 (t, J = 5.1Hz, 2H), 4.28 (s, 4H), 3.96 (t, J = 5.1Hz, 2H), 1.69 (s, 6H).

[0552] Example 85: Preparation of Compound 85

[0553] Preparation of compound 85

[0554] 3-Methanesulfonyl-azetidine (29.29 mg, 216.66 μmol), compound 15-2 (80 mg, 144.44 μmol), DIPEA (187 mg, 1.44 mmol, 251.6 μL), and acetonitrile were added to a reaction flask and stirred in a microwave oven at 80°C for 2 hours. The mixture was then dried and the crude product was purified by preparative liquid chromatography (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Agilent 10 Prep-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-80% acetonitrile over 12 minutes; flow rate: 20 mL / min) to obtain 50 mg of the title compound 54. LC-MS (ESI): m / z 652.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.46-8.41 (m, 2H), 7.95 (d, J=8.6Hz, 2H), 7.89 (d, J=8.8Hz , 1H), 7.70 (d, J=2.3Hz, 1H), 7.62 (d, J=2.4Hz, 1H), 7.53 (dd, J=8.8, 3.0Hz, 1H), 7. 33(d, J=8.6Hz, 2H), 6.90(d, J=5.0Hz, 1H), 5.18(s, 2H), 4.46-4.38(m, 3H), 4.34(t , J=8.6Hz, 2H), 4.28-4.17 (m, 2H), 3.96 (t, J=5.2Hz, 2H), 3.06 (s, 3H), 1.69 (s, 6H).

[0555] Example 86: Preparation of Compound 86

[0556] Preparation of compound 86-2

[0557] Compound 15-2 (500 mg, 902.75 μmol), compound 86-1 (317 mg, 1.35 mmol), DIPEA (350 mg, 2.71 mmol, 472 μL), Xantphos (105 mg, 180.55 μmol), Pd2(dba)3 (83 mg, 90.27 μmol), and dioxane (5 mL) were placed in a microwave tube and stirred at 100°C under nitrogen for 2 hours. The mixture was dried and the crude product was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to obtain 300 mg of the title compound 86-2, in a 44% yield. LC-MS (ESI): m / z 751.4 [M+H] + .

[0558] Preparation of Compound 86

[0559] Compound 86-2 (300 mg, 399.08 μmol) and DCM (10 mL) were added to a reaction flask, followed by the addition of TFA (455 mg, 3.99 mmol) and stirring at room temperature for 2 hours. The mixture was then dried and the crude product was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 220 mg of the title compound 86. LC-MS (ESI): m / z 651.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.47 (d, J=5.0Hz, 1H), 8.44 (d, J=3.0Hz, 1H), 7.95 (d, J=8.5Hz, 2 H), 7.89 (d, J=8.8Hz, 1H), 7.70 (d, J=2.4Hz, 1H), 7.63 (d, J=2.3Hz, 1H), 7.52 (dd, J=8.8, 3.0Hz, 1H), 7.33 (d, J=8.6Hz, 2H), 7.01 (d, J=5.0Hz, 1H), 5.20 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 3.74-3.59 (m, 2H), 3.45-3.34 (m, 2H), 3.28-3.18 (m, 2H), 3.15 -2.97 (m, 2H), 1.69 (s, 6H).

[0560] Example 87: Preparation of Compound 87

[0561] Preparation of Compound 87

[0562] Compound 1-8 (100 mg, 0.23 mmol) was dissolved in THF (5 mL), along with compound 87-1 (33 mg, 0.26 mmol) and PPh3 (123 mg, 0.47 mmol). The atmosphere was purged with nitrogen three times. DIAD (95 mg, 0.47 mmol) was added to the reaction system at 80°C and stirred overnight. After completion of the reaction, water (20 mL) was added, the THF was partially removed by vortexing, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was then purified by preparative separation (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 45% to 65% acetonitrile over 12 minutes; elution with acetonitrile over 12 minutes, flow rate: 30 mL / min) to yield 12 mg of the title compound 87. LC-MS (ESI): m / z 536.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.94 (d, J=0.9Hz, 2H), 7.70 (d, J=2.3Hz, 1H), 7.64 (d, J=2.4Hz, 1H), 7.60-7.51 (m, 3H), 7.45 (m, 1H ), 7.30 (d, J = 8.4Hz, 2H), 7.05 (d, J = 8.8Hz, 2H), 5.33 (s, 2H), 4.41 (t, J = 5.3Hz, 2H), 3.96 (t, J = 5.3Hz, 2H), 1.68 (s, 6H).19F NMR (376MHz, DMSO-d6) delta -138.90.

[0563] Example 88: Preparation of Compound 88

[0564] Preparation of compound 88-2

[0565] Compound 1-7 (100 mg, 0.20 mmol), compound 88-1 (66 mg, 0.27 mmol), potassium carbonate (44 mg, 0.57 mmol), and Pd(dppf)Cl2 (15 mg, 0.02 mmol) were dissolved in 1,4-dioxane (6 mL) and water (2 mL). The atmosphere was purged with nitrogen three times, and the reaction system was stirred in a microwave oven at 90°C for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered through a pad of celite, and the filter cake was rinsed with ethyl acetate (30 mL). The filtrates were combined, added with water (30 mL), and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by silica gel column chromatography (EA / PE = 0-25%) to obtain 90 mg of the title compound 88-2. LC-MS (ESI): m / z 451.0 [M+H] + .

[0566] Preparation of compound 88-3

[0567] Compound 88-2 (50 mg, 0.11 mmol) was dissolved in DMF (2 mL), and 2,4-dichloropyrimidine (20 mg, 0.13 mmol) and cesium carbonate (73 mg, 0.22 mmol) were added sequentially. The reaction system was stirred at room temperature for 2 hours. After the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel chromatography (EA / PE = 0-25%) to obtain 60 mg of the title compound 5. LC-MS (ESI): m / z 563.2 [M+H] + .

[0568] Preparation of Compound 88

[0569] Compound 88-3 (60 mg, 0.11 mmol), dimethylphosphine oxide (12 mg, 0.16 mmol), DIPEA (69 mg, 0.53 mmol), Xantphos (12 mg, 0.02 mmol), and Pd2(dba)3 (10 mg, 0.01 mmol) were dissolved in 1,4-dioxane (2 mL). The atmosphere was purged with nitrogen three times, and the reaction system was stirred in a microwave at 120°C for 2 hours. After completion of the reaction, the reaction solution was filtered through a pad of Celite, and the filtrate was rinsed with ethyl acetate (30 mL). The filtrates were combined, extracted three times with water (30 mL), and ethyl acetate (50 mL). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was then purified by preparative separation (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 45% to 65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 20.7 mg of the title compound 88. LC-MS (ESI): m / z 605.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.97 (d, J=6.0Hz, 1H), 8.33 (d, J=2.3Hz, 1H), 8.15 (dd, J=8.7, 2.4Hz, 1H), 7.76 (d, J=8.5Hz, 2H), 7.72 (d, J=2.4Hz, 1H), 7.69 -7.64 (m, 2H), 7.52 (dd, J=5.8, 2.6Hz, 1H), 7.39 (d, J=8.5Hz, 2H), 4.43 (t, J=5.6Hz, 2H), 3.96 (t, J=5.6Hz, 2H), 1.71 (s, 6H), 1.62 (d, J=13.8Hz, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.36.

[0570] Example 89: Preparation of Compound 89

[0571] Preparation of compound 89

[0572] Compound 88-2 (50 mg, 0.11 mmol) was dissolved in THF (5 mL), along with compound 89-1 (33 mg, 0.13 mmol) and Cs2CO3 (72 mg, 0.22 mmol). The reaction system was stirred at 60°C overnight. After completion of the reaction, water (25 mL) was added and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was then purified by preparative separation (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; acetonitrile over 12 minutes, flow rate: 30 mL / min) to afford 10 mg of the title compound 89. LC-MS (ESI): m / z 549.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.03 (d, J=2.4Hz, 1H), 7.95 (dd, J=8.9, 2.4Hz, 1H), 7.70 (d, J=2.3Hz, 1H), 7.67-7.58 (m, 3H), 7.33 (d, J=8.5Hz, 3H), 4.42 (t, J=5 .2Hz, 2H), 4.05 (d, J=6.4Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 3.93-3.86 (m, 2H), 3.49-3.21 (m, 1H), 2.18-1.93 (m, 2H), 1.77-1.60 (m, 8H), 1.45-1.31 (m, 2H).

[0573] Example 90: Preparation of Compound 90

[0574] Preparation of Compound 90-2

[0575] Compound 7-1 (90 mg, 0.16 mmol) and compound 90-1 (56 mg, 0.16 mmol) were dissolved in acetonitrile (10 mL) and potassium carbonate (66 mg, 0.48 mmol) was added. After the addition, the reaction system was stirred at 60°C for 3 hours. LCMS monitoring showed that the reaction of the starting material was complete. Water (20 mL) was added and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by column chromatography (EA / PE = 0-50%) to obtain 100 mg of the title compound 90-2. LC-MS (ESI): m / z 702.4 [M+H] + .

[0576] Preparation of Compound 90-3

[0577] Compound 90-2 (100 mg, 0.14 mmol) was dissolved in DCM (5 mL) and HCl solution (3 M, 5 mL) was added. The reaction system was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was directly dried to obtain the crude product of the title compound 90-3. This product was used directly in the next step without purification. LC-MS (ESI): m / z 602.2 [M+H] + .

[0578] Preparation of Compound 90

[0579] Compound 90-3 (100 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL), and methylsulfonyl chloride (23 mg, 0.20 mmol) and triethylamine (52 mg, 0.51 mmol) were added sequentially. The reaction system was stirred at 25°C for 1 hour. After completion of the reaction, water (10 mL) was added and the mixture was extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 23 mg of the title compound 90. LC-MS (ESI): m / z 680.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.32 (d, J=5.4Hz, 1H), 7.56-7.44 (m, 5H), 7.37 (d, J=2.3Hz, 1H), 7.22 (d, J=8.4Hz, 2H), 7.01 (d, J=8.7Hz, 2H), 6.94 (d, J=5.3Hz, 1H), 5.06 (s, 2H), 4.49-4.32 (m, 4H), 4.20 (d, J=9.5Hz, 2H), 3.88 (t, J=6.2Hz, 2H), 3.09 (s, 3H), 1.81 (s, 3H), 1.69 (s, 6H).

[0580] Example 91: Preparation of Compound 91

[0581] Preparation of compound 91-2

[0582] Compound 56-1 (250 mg, 0.56 mmol), compound 91-1 (145 mg, 0.67 mmol), and cyanomethylenetri-n-butylphosphine (270 mg, 1.12 mmol) were dissolved in toluene (20 mL). The reaction system was stirred at 100°C for 16 hours. After the reaction, water (10 mL) was added and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Purification by column chromatography (EA / PE = 0-30%) gave 200 mg of the title compound 91-2. LC-MS (ESI): m / z 578.2 [M+H-56] + .

[0583] Preparation of compound 91-3

[0584] Compound 91-2 (200 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL) and a 4 M solution of hydrogen chloride in 1,4-dioxane (10 mL) was added at 0°C. The reaction system was stirred at 25°C for 1 hour. After completion of the reaction, the solvent was concentrated to dryness to obtain the crude title compound 91-3. This product was used directly in the next step without purification. LC-MS (ESI): m / z 534.2 [M+H] + .

[0585] Preparation of compound 91-5

[0586] Compound 91-3 (200 mg, 0.37 mmol) was dissolved in methanol (10 mL), and compound 91-4 (85 mg, 0.44 mmol) and triethylamine (75 mg, 0.74 mmol) were added sequentially. The reaction system was stirred at 25°C for 1 hour. After completion of the reaction, water (10 mL) was added and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Purification by column chromatography (EA / PE = 0-70%) afforded 80 mg of the title compound 91-5. LC-MS (ESI): m / z 690.2 [M+H] + .

[0587] Preparation of Compound 91

[0588] Compound 91-5 (60 mg, 0.09 mmol) was dissolved in acetonitrile (5 mL), and dimethylphosphine oxide (21 mg, 0.27 mmol) and potassium carbonate (37 mg, 0.27 mmol) were added sequentially. The reaction system was stirred at 80°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, and the insoluble solids were filtered out. The filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; chromatographic column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 40%-60% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 13.4 mg of the title compound 91. LC-MS (ESI): m / z 688.3 [M+H] + . 1 H NMR (400MHz, Methanol-d4) δ8.28 (dd, J=6.5, 1.5Hz, IH), 7.96-7.85 (m, 2H), 7.63-7.49 (m, 4H), 7.41-7.30 (m, 3H), 6.91 (dd, J=6.4, 3.3Hz, 1H), 5.03 -4.93 (m, 1H), 4.43 (t, J = 5.2Hz, 2H), 4.06-3.81 (m, 6H), 2.17-2.04 (m, 2H), 2.01-1.89 (m, 2H), 1.83 (d, J = 13.7Hz, 6H), 1.72 (s, 6H). 31 P NMR (162MHz, Methanol-d4) δ 40.87 (s, 1P).

[0589] Example 92: Preparation of Compound 92

[0590] Preparation of compound 92

[0591] Compound 91-5 (60 mg, 0.09 mmol) was dissolved in acetonitrile (5 mL), and 3-(methylsulfonyl)azetidine (36 mg, 0.27 mmol) and potassium carbonate (37 mg, 0.27 mmol) were added sequentially. The reaction system was stirred at 80°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, the insoluble solid was filtered off, and the filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was then purified by preparative separation (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 40% to 60% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 2.1 mg of the title compound 92. LC-MS (ESI): m / z 745.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.86 (d, J=6.8Hz, 1H), 7.80 (d, J=2.3Hz, 1H), 7.75 (dd, J=8.7, 2.4Hz, 1H), 7.49 -7.43 (m, 3H), 7.34 (d, J = 2.4Hz, 1H), 7.28 (s, 2H), 7.09 (d, J = 8.8Hz, 1H), 6.11 (d, J = 6.9Hz, 1H), 4.85 (s, 1H), 4.57 (s, 4H), 4.4 3 (t, J=6.1Hz, 2H), 4.14-3.91 (m, 3H), 3.88 (t, J=6.1Hz, 2H), 3.84-3.76 (m, 2H), 2.96 (s, 3H), 2.09-1.98 (m, 4H), 1.70 (s, 6H).

[0592] Example 93: Preparation of Compound 93

[0593] Preparation of compound 93-2

[0594] Compound 7-1 (90 mg, 0.16 mmol) and compound 93-1 (56 mg, 0.16 mmol) were dissolved in acetonitrile (10 mL), and potassium carbonate (66 mg, 0.48 mmol) was added. After the addition, the reaction system was stirred at 60°C for 3 hours. LCMS monitored the complete reaction of the starting material. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by column chromatography (EA / PE = 0-50%) to obtain 100 mg of the title compound 93-2. LC-MS (ESI): m / z 702.3 [M+H] + .

[0595] Preparation of compound 93-3

[0596] Compound 93-2 (100 mg, 0.14 mmol) was dissolved in DCM (5 mL) and hydrochloric acid solution (3 M, 5 mL) was added. The reaction system was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was concentrated to obtain the crude product of the title compound 93-3, which was used directly in the next reaction without purification. LC-MS (ESI): m / z 602.2 [M+H] + .

[0597] Preparation of compound 93

[0598] Compound 93-3 (100 mg, 0.17 mmol) was dissolved in dichloromethane (10 mL), and methanesulfonyl chloride (23 mg, 0.20 mmol) and triethylamine (52 mg, 0.51 mmol) were added sequentially. The reaction system was stirred at 25°C for 1 hour. After completion of the reaction, water (10 mL) was added and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 23.6 mg of the title compound 93. LC-MS (ESI): m / z 680.2 [M+H] + . 1H NMR (400MHz, Chloroform-d) δ8.35 (d, J=5.2Hz, 1H), 7.53 (d, J=8.8Hz, 2H), 7. 50-7.45 (m, 3H), 7.37 (d, J = 2.4Hz, 1H), 7.22 (d, J = 8.4Hz, 2H), 7.01 (d, J = 8.8H z, 2H), 6.92 (d, J=5.1Hz, 1H), 5.05 (s, 2H), 4.91-4.81 (m, 1H), 4.51-4.39 (m, 4 H), 4.31 (s, 2H), 3.88 (t, J=6.2Hz, 2H), 3.03 (s, 3H), 2.84 (s, 3H), 1.69 (s, 6H).

[0599] Example 94:- Preparation of Compound 94

[0600] Preparation of Compound 94

[0601] Compound 7-1 (30 mg, 0.054 mmol) was dissolved in acetonitrile (2 mL), and potassium carbonate (15 mg, 0.108 mmol) and 94-1 (9 mg, 0.054 mmol) were added sequentially. The reaction system was stirred at 80°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, and the insoluble solids were filtered out. The filtrate was concentrated to obtain the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 5 mg of the title compound 94. LC-MS (ESI): m / z 679.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.39 (d, J=4.9Hz, 1H), 7.70 (d, J=2.3Hz, 1H), 7.63 (d, J=2.3Hz, 1H), 7.5 9 (d, J=8.8Hz, 2H), 7.55 (d, J=8.4Hz, 2H), 7.30 (d, J=8.5Hz, 2H), 7.07 (d, J=8.8Hz, 2H), 6.73 (d, J =5.0Hz, 1H), 5.07 (s, 2H), 4.89-4.76 (m, 2H), 4.42 (t, J = 5.2Hz, 2H), 3.96 (t, J = 5.2Hz, 2H), 3.47- 3.36 (m, 1H), 3.06-2.85 (m, 2H), 2.94 (s, 3H), 2.15-2.00 (m, 2H), 1.68 (s, 6H), 1.60-1.41 (m, 2H).

[0602] Example 95: Preparation of Compound 95

[0603] Preparation of compound 95-2

[0604] Compound 12-3 (100 mg, 0.497 mmol) was dissolved in 1,4-dioxane (10 mL) and water (3 mL). Compound 95-1 (460 mg, 0.229 mmol), potassium carbonate (172 mg, 1.24 mmol), and Pd(dppf)Cl2 (36 mg, 0.050 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the reaction system was stirred at 91°C for 2 hours. After the reaction, water (30 mL) was added and extracted three times with ethyl acetate (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by column chromatography (EA / PE = 0-20%) to obtain 210 mg of the title compound 95-2 in a 93% yield. LC-MS (ESI): m / z 454.0 [M+H] + .

[0605] Preparation of compound 95

[0606] Compound 95-2 (210 mg, 0.462 mmol) was dissolved in acetonitrile (8 mL), and potassium carbonate (128 mg, 0.924 mmol) and 95-3 (186 mg, 0.462 mmol) were added sequentially. The reaction system was stirred at 70°C for 0.5 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was concentrated to obtain the crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 5 mg of the title compound 95. LC-MS (ESI): m / z 620.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.98 (d, J=5.2Hz, 1H), 8.73 (d, J=2.5Hz, 1H), 8.71 (d, J=2.5Hz, 1H), 7.71-7.63 (m, 5H), 7.3 6 (d, J=8.5Hz, 2H), 5.74 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 3.95 (t, J=5.2Hz, 2H), 1.70 (d, J=13.6Hz, 6H), 1.69 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.17.

[0607] Example 96: Preparation of Compound 96

[0608] Preparation of compound 96-2

[0609] 2-Bromo-5-fluoropyrazine (380 mg, 2.15 mmol), compound 12-3 (988.1 mg, 2.15 mmol), Pd(dppf)Cl2 (157 mg, 214.72 μmol), and potassium carbonate (741 mg, 5.37 mmol) were weighed and added to a mixed solvent of H2O (5 mL) and 1,4-dioxane (15 mL). After nitrogen substitution three times, the mixture was reacted at 100°C for 5 hours. LCMS analysis revealed that the reaction was complete. The reaction solution was poured into ice water and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain the crude product. Purification by normal phase silica gel chromatography (EA / PE = 0-40%) afforded 750 mg of the title compound 96-2 in an 81% yield. LC-MS (ESI): m / z 430.2 [M+H]. + .

[0610] Preparation of compound 96-3

[0611] Compound (2-(methylthio)pyrimidin-4-yl)methanol (279 mg, 1.78 mmol) was added to anhydrous tetrahydrofuran (20 mL). Sodium hydride (142.8 mg, 5.95 mmol, 60% purity) was added under an ice-water bath. After 5 minutes of reaction, compound 96-2 (640 mg, 1.49 mmol) was added and the mixture was allowed to react at room temperature for 3 hours. LCMS analysis revealed that the reaction was complete. The reaction solution was poured into ice water and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (EA / PE = 0-40%) to afford 560 mg of the title compound 96-3 in a 66.5% yield. LC-MS (ESI): m / z 566.3 [M+H]. + .

[0612] Preparation of compound 96-4

[0613] Compound 96-3 (250 mg, 441.31 μmol) was weighed in dichloromethane (10 mL), and m-CPBA (305 mg, 1.77 mmol) was added with stirring. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction as monitored by LCMS, the reaction solution was poured into ice water, extracted with dichloromethane (20 mL x 2), and washed with saturated sodium bicarbonate solution. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (EA / PE = 0-80%) to obtain 250 mg of the title compound 96-4 in a 95% yield. LC-MS (ESI): m / z 598.2 [M+H] + .

[0614] Preparation of Compound 96

[0615] Compound 96-4 (180 mg, 300.75 μmol) and cesium carbonate (196 mg, 601.50 μmol) were weighed and added to acetonitrile (8 mL). After stirring for 5 minutes, dimethylphosphine oxide (47 mg, 601.50 μmol) was added. The reaction was allowed to proceed at 60°C for 2 hours. After completion of the reaction as monitored by LCMS, the mixture was cooled to a temperature below 50°C, filtered, and the filtrate purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 24 mg of the title compound 96. LC-MS (ESI): m / z 596.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.95 (d, J=5.2Hz, 1H), 8.74 (d, J=1.4Hz, 1H), 8.59 (d, J=1.4Hz, 1H), 7.96 (d, J=8.5Hz, 2H), 7.73-7.66 (m, 2H), 7.6 3 (d, J=2.3Hz, 1H), 7.37 (d, J=8.6Hz, 2H), 5.63 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 1.72 (d, J=13.7Hz, 6H), 1.69 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.12 (s, 1P).

[0616] Example 97: Preparation of Compound 97

[0617] Preparation of Compound 97-1

[0618] Compound 1-8 (200 mg, 469.12 μmol) was added to a three-necked flask, followed by anhydrous DCM (10 mL), (2-chloropyrimidin-5-yl)methanol (88 mg, 609.85 μmol), and N,N,N′,N′-tetramethylazodicarbonamide (162 mg, 938.23 μmol). The atmosphere was replaced with nitrogen three times, and tributylphosphine (190 mg, 938.23 μmol) was added at 0°C. The reaction was stirred at 25°C for 3 hours. After completion of the reaction, water (20 mL) was added, and the mixture was extracted with DCM (20 mL x 2). The organic phases were combined, dried, and concentrated to obtain the crude product, which was purified by silica gel column chromatography (EtOAc / PE = 0-30%) to afford 100 mg of the title compound 97-1 in a 38.6% yield. LC-MS (ESI): 552.1 [M+H] + .

[0619] Preparation of Compound 97

[0620] Compound 97-1 (60 mg, 108.52 μmol) was dissolved in DMF (2 mL), and tris(dibenzylideneacetone)dipalladium (10 mg, 10.85 μmol), 4,5-bis(diphenyl)phosphine-9,9-dimethylxanthene (13 mg, 21.70 μmol), DIPEA (42 mg, 325.57 μmol), and dimethylphosphine oxide (25 mg, 325.57 μmol) were added sequentially. The reaction system was stirred at 120°C for 3 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was added with water (10 mL) and extracted three times with dichloromethane (20 mL). The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) afforded 30 mg of the title compound 97. LC-MS (ESI): m / z 594.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.09 (s, 2H), 7.70 (d, J=2.3Hz, 1H), 7.66-7.59 (m, 3H), 7.57 (d, J=8.5Hz, 2H), 7.30 (d, J=8.5Hz, 2 H), 7.14 (d, J=8.8Hz, 2H), 5.31 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 1.77 (d, J=13.7Hz, 6H), 1.68 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.02 (s, 1P).

[0621] Example 98: Preparation of Compound 98

[0622] Preparation of Compound 98

[0623] Compound 96-4 (60 mg, 100.25 μmol) and DIPEA (26 mg, 200.50 μmol) were dissolved in acetonitrile (3 mL) and stirred for 5 minutes. 2-Oxa-6-azaspiro[3.3]heptane (15 mg, 150.38 μmol) was then added and the mixture was allowed to react at 60°C for 2 hours. The reaction was monitored by LCMS until completion. The reaction mixture was filtered, and the crude filtrate was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 35 mg of the title compound 98. LC-MS (ESI): m / z 617.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.74 (d, J=1.4Hz, 1H), 8.52 (d, J=1.3Hz, 1H), 8.31 ( d, J=5.0Hz, 1H), 7.96 (d, J=8.5Hz, 2H), 7.70 (d, J=2.3Hz, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.37 (d, J=8.5Hz, 2H), 6.70 (d, J=5.0Hz, 1H), 5.33 (s, 2H), 4.70 (s, 4H), 4.42 (t, J=5.2Hz, 2H), 4.18 (s, 4H), 3.95 (t, J=5.2Hz, 2H), 1.69 (s, 6H).

[0624] Example 99: Preparation of Compound 99

[0625] Preparation of Compound 99-2

[0626] Compound 99-1 (60 mg, 220.47 μmol), compound 56-1 (109 mg, 24 μmol), and cesium carbonate (143 mg, 440 μmol) were dissolved in acetonitrile (2 mL). After nitrogen substitution three times, the mixture was stirred at 75°C for 3 hours. After completion of the reaction, water (15 mL) was added and extracted three times with dichloromethane (15 mL). The organic phases were combined, washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (EA / PE = 0-20%) to obtain 105 mg of the title compound 99-2. LC-MS (ESI): m / z 625.1 [M+H] + .

[0627] Preparation of Compound 99

[0628] Compound 99-2 (85 mg, 141.1 μmol) was dissolved in DMF (2 mL), and Pd2(dba)3 (5.16 mg, 7.06 μmol), 4,5-bis(diphenyl)phosphine-9,9-dimethylxanthene (4 mg, 7.06 μmol), DIPEA (36 mg, 282.22 μmol, 49.16 μL), and dimethylphosphine oxide (22 mg, 282.22 μmol) were added sequentially. The reaction was stirred in a microwave oven at 120°C for 2 hours. After completion of the reaction, the insoluble solid was filtered off, and the filtrate was added with water (10 mL) and extracted three times with dichloromethane (10 mL). The organic phases were combined, washed twice with saturated brine (15 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 10% to 45% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 13 mg of the title compound 99. LC-MS (ESI): m / z 624.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.27 (s, 1H), 8.08 (d, J=2.4Hz, 1H), 8.00 (dd, J=8.9, 2.4Hz, 1H), 7.70 (d, J=2.3Hz, 1H), 7.68-7.59 (m, 3H), 7.51 (d, J=9.0Hz, 1H), 7.33 (d, J=8.5Hz, 2H), 6.00 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 1.75 (d, J=13.9Hz, 6H), 1.68 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.17 (s, 1P).

[0629] Example 100: Preparation of Compound 100

[0630] Preparation of Compound 100-2

[0631] Compound 42-6 (620 mg, 1.58 mmol) and cyanomethylenetri-n-butylphosphine (572 mg, 2.37 mmol) were dissolved in toluene (7 mL), and the reaction system was stirred at 100°C for 3 hours. After the reaction was completed, the reaction system was cooled to room temperature and filtered. A saturated aqueous sodium chloride solution (15 mL) was added to the filtrate, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (EtOAc / PE = 0-30%) to obtain 580 mg of the off-white title compound 100-2, in a 63% yield. LC-MS (ESI): 575.4 [M+H] + .

[0632] Preparation of Compound 100-3

[0633] Compound 100-2 (580 mg, 1.01 mol) was added to dichloromethane (6 mL), and trifluoromethanesulfonic acid (0.5 mL) was added dropwise under ice-cooling. The reaction system was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated to obtain 460 mg of crude title compound 100-3, with a yield of 96%. LC-MS (ESI): 475.3 [M+H] + .

[0634] Preparation of Compound 100-4

[0635] Compound 100-3 (200 mg, 421 μmol) and triethylamine (92 mg, 842 μmol) were dissolved in DCM (6 mL). 4-Chloro-2-(methylsulfonyl)pyrimidine (97 mg, 505 μmol) was added portionwise under ice-cooling. The reaction system was stirred at room temperature for 2 hours. After completion of the reaction, the reaction system was filtered, and a saturated aqueous sodium chloride solution (10 mL) was added to the filtrate. The mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (EtOAc / PE = 0-20%) to afford 165 mg of the title compound 100-4 as a white solid in a 62% yield. LC-MS (ESI): 631.2 [M+H] + .

[0636] Preparation of Compound 100

[0637] Compound 100-4 (90 mg, 142 μmol), dimethylphosphine oxide (33 mg, 426 μmol), and cesium carbonate (93 mg, 284 μmol) were added to acetonitrile (3 mL), and the reaction system was stirred at 70°C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, saturated brine (5 mL) was added, and extraction was performed three times with EA (8 mL). The organic phases were combined, dried, and concentrated to obtain the crude product, which was then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-30% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 18 mg of the title compound 100. LC-MS (ESI): m / z 629.5 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.40 (d, J=2.2Hz, 1H), 8.29 (dd, J=6.3, 1.3Hz, 1H), 8. 19 (d, J=2.3Hz, 1H), 8.17 (s, 1H), 7.63-7.48 (m, 4H), 7.31 (d, J=8.5Hz, 2H), 7.0 8(d, J=8.8Hz, 2H), 6.96 (dd, J=6.4, 3.1Hz, 1H), 4.78-4.68 (m, 3H), 4.19-3.96 (m, 4H), 3.61-3.49 (m, 2H), 2.10-1.98 (m, 2H), 1.78 (s, 6H), 1.72-1.58 (m, 8H). 31 P NMR (162MHz, DMSO-d6) δ33.57.

[0638] Example 101: Preparation of Compound 101

[0639] Preparation of Compound 101-2

[0640] Compound 101-1 (100 mg, 1.0 mol) was added to dichloromethane (2 mL), and trifluoromethanesulfonic acid (0.3 mL) was added dropwise under ice-cooling. The reaction system was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated to obtain 110 mg of the crude title compound with a yield of 92%.

[0641] Preparation of Compound 101

[0642] Compound 101-2 (15 mg, 148.31 μmol), compound 7-1 (41 mg, 74.16 μmol), and TEA (15 mg, 148.31 μmol) were added to acetonitrile (2 mL). The reaction system was stirred at 70°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, saturated brine (5 mL) was added, and extraction was performed three times with EA (8 mL). The organic phases were combined, dried, filtered, and concentrated to obtain the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-30% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 11 mg of the title compound 101 in a 17% yield. LC-MS (ESI): m / z 616.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.46 (d, J=5.0Hz, 1H), 7.70 (d, J=2.4Hz, 1H), 7.64 (d, J=2.3Hz, 1H) , 7.60 (d, J = 8.8Hz, 2H), 7.56 (d, J = 8.4Hz, 2H), 7.30 (d, J = 8.5Hz, 2H), 7.08 (d, J = 8.8Hz, 2H) , 6.95 (d, J=5.0Hz, 1H), 5.10 (s, 2H), 4.74 (dd, J=11.2, 1.6Hz, 1H), 4.69 (dd, J=11.2, 1.6Hz , 1H), 4.48 (dd, J=11.3, 1.6Hz, 1H), 4.46-4.38 (m, 3H), 3.96 (t, J=5.2Hz, 2H), 1.68 (s, 6H).

[0643] Example 102: Preparation of Compound 102

[0644] Preparation of Compound 102

[0645] Compound 7-1 (65 mg, 117.57 μmol), 3-(difluoromethoxy)azetidine (18 mg, 141 μmol), and TEA (24 mg, 235.13 μmol) were added to acetonitrile (2 mL). The reaction system was stirred at 90°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, saturated brine (5 mL) was added, and the mixture was extracted three times with EA (8 mL). The organic phases were combined, dried, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-30% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 14 mg of the title compound 102. LC-MS (ESI): m / z 639.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.39 (dJ=5.0Hz, 1H), 7.70 (d, J=2.3Hz, 1H), 7.64 (d, J =2.4Hz, 1H), 7.59 (d, J = 8.7Hz, 2H), 7.55 (d, J = 8.4Hz, 2H), 7.30 (d, J = 8.4Hz, 2 H), 7.07 (d, J=8.8Hz, 2H), 6.82 (d, J=5.0Hz, 1H), 6.80 (d, J=74.8Hz, 1H), 5.13 -5.00 (m, 1H), 5.08 (s, 2H), 4.46-4.33 (m, 4H), 4.07-3.89 (m, 4H), 1.68 (s, 6H).

[0646] Example 103: Preparation of Compound 103

[0647] Preparation of Compound 103-1

[0648] Dissolve tert-butyl 4-hydroxypiperidine-1-carboxylate (500 mg, 2.48 mmol) in tetrahydrofuran (5 mL). After nitrogen substitution three times, sodium hydroxide (149 mg, 3.72 mmol, 60% purity) was added in an ice bath. After 30 minutes, 2-fluoro-5-iodopyridine (663 mg, 2.98 mmol) was added, and the reaction system was stirred at 15°C for 15 hours. After completion of the reaction, filter, add saturated aqueous sodium chloride solution (15 mL) to the filtrate, and extract three times with ethyl acetate (10 mL). The organic phases were combined, dried, and concentrated to obtain the crude product, which was purified by silica gel column chromatography (EtOAc / PE = 0-30%) to afford 470 mg of the off-white title compound 103-1 in a 46.8% yield. LC-MS (ESI): 405.2 [M+H]+ .

[0649] Preparation of Compound 103-2

[0650] Compound 103-1 (470 mg, 1.16 mmol) was dissolved in 1,4-dioxane (10 mL), and cesium carbonate (754 mg, 2.32 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (46 mg, 5.8 μmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the mixture was stirred at 105°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and filtered. A saturated aqueous sodium chloride solution (20 mL) was added to the filtrate, and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (EtOAc / PE = 0-40%) to give 320 mg of the off-white title compound 103-2 in a 45% yield. LC-MS (ESI): 610.2 [M+H]. + .

[0651] Preparation of Compound 103-3

[0652] Compound 103-2 (320 mg, 524 μmol) was added to dichloromethane (6 mL), and trifluoromethanesulfonic acid (0.5 mL) was added dropwise under ice-cooling. The reaction system was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated to obtain 255 mg of crude product of the title compound 103-3, with a yield of 95%.

[0653] Preparation of compound 103-4

[0654] Compound 103-3 (255 mg, 499 μmol) and triethylamine (101 mg, 998 μmol) were dissolved in DCM (4 mL). 4-Chloro-2-(methylsulfonyl)pyrimidine (98 mg, 505 mol) was added portionwise under ice-cooling and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was filtered, and a saturated aqueous sodium chloride solution (10 mL) was added to the filtrate. The mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (EtOAc / PE = 0-20%) to afford 206 mg of the title compound 103-4, in a 61% yield. LC-MS (ESI): 666.4 [M+H] + .

[0655] Preparation of Compound 103

[0656] Compound 103-4 (100 mg, 150 μmol), dimethylphosphine oxide (35 mg, 450 μmol), and cesium carbonate (98 mg, 300 μmol) were added to acetonitrile (3 mL) and stirred at 90°C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, saturated brine (10 mL) was added, and extraction was performed three times with EA (10 mL). The organic phases were combined, dried, and filtered, and the filtrate was concentrated to obtain the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 10%-30% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 22 mg of the title compound. LC-MS (ESI): m / z 664.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.47 (s, 1H), 8.30 (dd, J=6.3, 1.2Hz, 1H), 8.01 (dd, J=8.6, 2.6Hz, 1H), 7.71 ( d, J=2.4Hz, 1H), 7.65 (d, J=2.3Hz, 1H), 7.60 (d, J=8.5Hz, 2H), 7.34 (d, J=8.5Hz, 2H), 6.97 (dd, J=6.4, 3.1Hz, 1H), 6.89 (d, J=8.6Hz, 1H), 5.40-5.27 (m, 1H), 4.42 (t, 2H), 4.23-4.03 (m, 2H), 3.96 (t, 2H), 3. 52 (t, J=11.1Hz, 2H), 3.44-3.36 (m, 2H), 2.09 (d, J=13.2Hz, 2H), 1.69 (s, 6H), 1.67 (d, J=13.6Hz, 6H). 31 P NMR (162MHz, DMSO-d6) δ33.56 (s, 1P).

[0657] Example 104: Preparation of Compound 104

[0658] Preparation of Compound 104-1

[0659] Compound 7-1 (30 mg, 0.054 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate (26 mg, 0.054 mmol) were dissolved in anhydrous acetonitrile (2 mL), and potassium carbonate (15 mg, 0.108 mmol) was added. The reaction system was stirred at 80°C for 12 hours. After completion of the reaction, the mixture was cooled to room temperature, the insoluble solids were filtered out, and the filtrate was concentrated to obtain the crude product. Purification by column chromatography (EA / PE = 0-20%) gave 38 mg of the crude title compound 104-1, with a yield of 98%. LC-MS (ESI): m / z 714.3 [M+H] + .

[0660] Preparation of Compound 104

[0661] Compound 104-1 (40 mg, 0.056 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise under ice-cooling. The reaction system was stirred and kept warm for 2 hours. After completion of the reaction, the crude product was concentrated. Preparative separation and purification (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) yielded 12 mg of the title compound 104. LC-MS (ESI): m / z 614.3 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.26 (d, J=5.1Hz, 1H), 7.48-7.38 (m, 5H), 7.31-7.29 (m, 1H), 7.17-7.12 (m, 2H), 6.97-6.90 (m, 2H), 6.80 (d, J=4.9Hz, 1H), 4.95 (s, 2H), 4.36 (t, J=6.2Hz, 2H), 4.27 (s, 4H), 4.23 (s, 4H), 3.81 (t, J=6.2Hz, 2H), 1.62 (s, 6H).

[0662] Example 105: Preparation of Compound 105

[0663] Preparation of Compound 105

[0664] Compound 104 (60 mg, 0.098 mmol) and triethylamine (39 mg, 0.390 mmol) were dissolved in dichloromethane (2 mL). The mixture was cooled to 0°C, and a solution of methanesulfonyl chloride (45 mg, 0.390 mmol) in dichloromethane (1 mL) was added dropwise. After the addition was complete, the reaction system was stirred at 0°C for 1 hour. After the reaction, the insoluble solids were filtered off, and the filtrate was concentrated to obtain the crude product, which was purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 25 mg of the title compound 105. LC-MS (ESI): m / z 692.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.36 (d, J=5.1Hz, 1H), 7.70 (s, 1H), 7.67-7.46 (m, 5H), 7.30 (d, J=8.0Hz, 2H), 7.07 (d, J=8.2Hz, 2H), 6.78 (d, J=5.1Hz, 1H), 5.05 (s, 2H), 4.42 (t, J=5.1Hz, 2H), 4.20 (s, 4H), 4.08 (s, 4H), 3.95 (t, J=5.2Hz, 2H), 3.01 (s, 3H), 1.68 (s, 6H).

[0665] Example 106: Preparation of Compound 106

[0666] Preparation of Compound 106-2

[0667] Compound 106-1 (50 mg, 0.26 mmol) was dissolved in tetrahydrofuran (1 mL) in a 25 mL two-necked flask. The mixture was cooled to 0°C under nitrogen and a solution of borane in tetrahydrofuran (0.32 mL, 0.32 mmol, 1 M) was slowly added. The reaction mixture was stirred at 0°C for 2 hours. After completion of the reaction, methanol was added to quench the reaction and the mixture was concentrated under reduced pressure to obtain 70 mg of crude title compound 106-2.

[0668] Preparation of Compound 106-3

[0669] Compound 106-2 (70 mg, 0.19 mmol) was dissolved in dichloromethane (2 mL) in a 25 mL two-necked flask. DMAP (2 mg, 0.02 mmol) and triethylamine (40 mg, 0.40 mmol) were added sequentially. p-Toluenesulfonyl chloride (45 mg, 0.24 mmol) was added under nitrogen at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (EA / PE = 0-20%) to yield 43 mg of the title compound 106-3. 1 H NMR (400MHz, Chloroform-d) δ7.81-7.73(m, 2H), 7.42-7.31(m, 2H), 4.12(s, 2H), 4.03(s, 2H) , 3.99 (d, J=5.4Hz, 2H), 2.68-2.59 (m, 1H), 2.46 (s, 3H), 2.44-2.36 (m, 2H), 2.23-2.14 (m, 2H).

[0670] Preparation of Compound 106

[0671] In a 25 mL single-necked vial, compound 106-3 (30 mg, 0.09 mmol) was dissolved in DMF (0.5 mL). Compound 1-8 (50 mg, 0.12 mmol) and cesium carbonate (59 mg, 0.18 mmol) were added sequentially. The reaction mixture was stirred at 80°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 13.4 mg of the title compound 106. LC-MS (ESI): m / z 584.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.70 (d, J=2.3Hz, 1H), 7.64 (d, J=2.3Hz, 1H), 7.56 (t, J=9.0Hz, 4H), 7.30 (d, J=8.5Hz, 2H), 7.00 (d, J=8.8Hz, 2H), 4.4 7-4.38(m, 2H), 4.27(s, 2H), 4.20(s, 2H), 4.05-3.88(m, 4H), 2.74-2.6 3 (m, 1H), 2.47-2.40 (m, 2H), 2.25-2.14 (m, 2H), 1.69 (d, J=6.8Hz, 6H).

[0672] Example 107: Preparation of Compound 107

[0673] Preparation of Compound 107

[0674] In a 25 mL single-necked bottle, compound 106-1 (50 mg, 0.26 mmol) was dissolved in dichloromethane (2 mL), and compound 1-8 (110 mg, 0.32 mmol), DMAP (3 mg, 0.03 mmol), DIPEA (68 mg, 0.53 mmol), and EDCI (60 mg, 0.32 mmol) were added in sequence. The mixture was stirred at room temperature for 16 hours. After the reaction, the reaction mixture was washed with water (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (EA / PE = 0-30%) and then purified by preparative separation (preparative method: mobile phase: A: 0.1% formic acid aqueous solution; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to obtain 61 mg of the title compound 107. LC-MS (ESI): m / z 598.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.76-7.67 (m, 3H), 7.65 (d, J=2.3Hz, 1H), 7.61 (d, J=8.1Hz, 2H), 7.34 (d, J=8.1Hz, 2H), 7.22 (d, J=8.7Hz, 2H ), 4.42 (t, J=5.1Hz, 2H), 4.33 (s, 2H), 4.24 (s, 2H), 3.96 (t, J=5.1Hz, 2H), 3.45 (p, J=8.5Hz, 1H), 2.66 (d, J=8.5Hz, 4H), 1.69 (s, 6H).

[0675] Example 108: Preparation of Compound 108

[0676] Preparation of Compound 108-1

[0677] Compound 7-1 (190 mg, 343.66 μmol) was dissolved in DMF (3 mL), and tris(dibenzylideneacetone)dipalladium (31.5 mg, 34.37 μmol), 4,5-bis(diphenyl)phosphine-9,9-dimethylxanthene (40 mg, 68.73 μmol), DIEA (133 mg, 1.03 mmol), and compound 86-1 (161 mg, 687.31 μmol) were added in sequence. The reaction system was stirred at 120°C for 3 hours. After the reaction was complete as monitored by LCMS, the reaction solution was poured into ice water and extracted twice with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (EA / PE = 0-40%) to obtain 150 mg of the title compound 108-1 in a 58% yield. LC-MS (ESI): m / z 750.4 [M+H] + .

[0678] Preparation of Compound 108

[0679] Compound 108-1 (130 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL). A solution of hydrogen chloride in 1,4-dioxane (5 mL, 4 M) was added dropwise with stirring. The mixture was allowed to react overnight at room temperature. The reaction was monitored by LCMS until completion, and the mixture was concentrated to obtain the crude product. This was then purified by preparative separation (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250×21.2 mm; column temperature: 25°C; gradient elution: 45%-65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 56 mg of the title compound 108. LC-MS (ESI): m / z 650.6 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.44 (d, J=5.0Hz, 1H), 7.70 (d, J=2.4Hz, 1H), 7.64 (d, J=2.3Hz, 1 H), 7.60 (d, J=8.8Hz, 2H), 7.55 (d, J=8.4Hz, 2H), 7.30 (d, J=8.4Hz, 2H), 7.07 (d, J=8.8Hz , 2H), 6.96 (d, J=5.1Hz, 1H), 5.10 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 3 .67-3.55(m, 2H), 3.32-3.26(m, 2H), 3.21-3.08(m, 2H), 3.05-2.92(m, 2H), 1.68(s, 6H).

[0680] Example 109: Preparation of Compound 109

[0681] Preparation of compound 109-

[0682] Compound 21-3 (190 mg, 343.66 μmol), 2-chloro-5-iodopyrimidine (161 mg, 687.31 μmol), bis(triphenyl)phosphine palladium dichloride (81 mg, 115.11 μmol), cuprous iodide (91 mg, 115.11 μmol), and triethylamine (582 mg, 5.76 mmol) were added to acetonitrile (10 mL) and stirred at 50°C for 4 hours. The reaction was monitored by LCMS until completion. The reaction solution was poured into ice water and extracted twice with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was purified by silica gel column chromatography (EA / PE = 0-40%) to obtain 100 mg of the title compound 109-1 in a 32% yield. LC-MS (ESI): m / z 546.2 [M+H]. + .

[0683] Preparation of Compound 109

[0684] Compound 109-1 (110 mg, 201.14 μmol) was dissolved in DMF (3 mL), and tris(dibenzylideneacetone)dipalladium (19 mg, 20.11 μmol), 4,5-bis(diphenyl)phosphine-9,9-dimethylxanthene (24 mg, 40.23 μmol), DIEA (78 mg, 603.43 μmol), and dimethylphosphine oxide (47 mg, 603.43 μmol) were added sequentially. The reaction system was stirred at 120°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, the insoluble solid was filtered off, and the filtrate was extracted with water (10 mL) and ethyl acetate (20 mL) three times. The organic phases were combined, washed twice with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was then purified by preparative separation (mobile phase: A: 0.1% formic acid in water; B: acetonitrile; column: Welch Ultimate AQ-C18 250 × 21.2 mm; column temperature: 25°C; gradient elution: 45% to 65% acetonitrile over 12 minutes; flow rate: 30 mL / min) to yield 45 mg of the title compound 109. LC-MS (ESI): m / z 588.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.19 (s, 2H), 7.81 (d, J = 8.5Hz, 2H), 7.72 (d, J = 8.4Hz, 2H), 7.71 (m, 1H), 7.70 (d, J = 8.4Hz, 2H), 7.65 (d, J=2.3Hz, 1H), 7.38 (d, J=8.5Hz, 2H), 4.43 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 1.79 (d, J=13.8Hz, 6H), 1.70 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.38 (s, 1P).

[0685] Example 110: Preparation of Compound 110

[0686] Preparation of compound 110-1

[0687] 4-Methyl-2-(methylthio)pyrimidine (10.2 g, 72.75 mmol) was dissolved in anhydrous THF (30 mL) under argon protection and cooled to -10°C. At this temperature, NaHMDS (1 M in THF, 218 mL, 218 mmol) was slowly added dropwise to the reaction system. The mixture was stirred at -10°C for 30 minutes. Diethyl carbonate (10.3 g, 87.31 mmol) was slowly added dropwise to the reaction system. After the addition was complete, the temperature was naturally warmed to room temperature and stirred for 3 hours. After completion, saturated aqueous ammonium chloride (100 mL) was added dropwise to quench the reaction, followed by addition of hydrochloric acid (100 mL, 2 M). The mixture was extracted three times with ethyl acetate (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (EA / PE = 0-30%) to afford 12.5 g of the light yellow title compound in an 81% yield. LC-MS (ESI): m / z [M+H] + :213.1.

[0688] Preparation of compound 110-2

[0689] Compound 110-1 (10.5 g, 49.47 mmol) was dissolved in anhydrous THF (50 mL). The temperature was lowered to -5°C under argon protection, and DIBAL-H (49.5 mL, 74.10 mmol, 1.5 M solution in toluene) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 2 hours. After the reaction, water (50 mL) was added and the mixture was extracted three times with ethyl acetate (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (EA / PE = 0-20%) to afford 4.5 g of the title compound 110-2 as a brown oil in a 36% yield. LC-MS (ESI): m / z [M+H] + :171.1.

[0690] Preparation of compound 110-3

[0691] Compound 110-2 (1 g, 5.87 mmol), 5-iodopyridazin-3(2H)-one (1.43 g, 6.46 mmol), and triphenylphosphine (1.43 g, 8.80 mmol) were dissolved in anhydrous THF (20 mL). Under argon protection, the temperature was cooled to 0°C, and DEAD (1.53 g, 8.80 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was naturally warmed to room temperature and stirred for 16 hours. After the reaction was completed, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (EA / PE = 0-40%) to afford 1.1 g of the title compound 110-3 as a white solid in a 50% yield. LC-MS (ESI): m / z 374.8 [M+H] + .

[0692] Preparation of compound 110-4

[0693] Compounds 12-3 (1.0 g, 2.17 mmol) and 110-3 (812 mg, 2.17 mmol) were dissolved in 1,4-dioxane (15 mL) and water (1 mL). [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (159 mg, 0.22 mmol) and potassium carbonate (900 mg, 6.51 mmol) were added. The argon atmosphere was replaced four times, and the mixture was heated to 110°C and stirred for 3 hours. After the reaction, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (EA / PE = 0-50%) to afford 660 mg of the title compound 110-4 as a yellow oil in a 52% yield. LC-MS (ESI): m / z 579.9 [M+H]. + .

[0694] Preparation of compound 110-5

[0695] Compound 110-4 (300 mg, 0.52 mmol) was dissolved in THF (2 mL) and water (2 mL), and potassium peroxymonosulfate (1.28 g, 2.08 mmol) was added. The mixture was stirred at room temperature for 16 hours. LCMS monitoring indicated the disappearance of the starting material. After the reaction was completed, water (10 mL) was added and the mixture was extracted three times with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 300 mg of the crude product of the title compound 110-5 in a yield of 95%. The product was used directly in the next reaction without purification.

[0696] Preparation of Compound 110

[0697] Compound 110-5 (300 mg, 0.49 mmol) and dimethylphosphine oxide (191 mg, 1.96 mmol) were dissolved in acetonitrile (3 mL). Potassium carbonate (271 mg, 3.72 mmol) was added at room temperature, and the mixture was heated to 70°C and stirred for 2 hours. LCMS was used to monitor the reaction until completion. Water (10 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL). The organic phases were combined and concentrated, and the resulting residue was purified by preparative separation (preparative column: Atlantis™ T3 prep OBD™, 19*250 mm*10 μm; flow rate: 20 mL / min; mobile phase: A-0.1% FA aqueous solution, B-acetonitrile; gradient: 56-64% acetonitrile content, retention time 7.4-8.0 min) to yield 21.7 mg of the title compound 110=. LC-MS (ESI): m / z 610.3 [M+H] + .

[0698] 1 H NMR (400MHz, DMSO-d6) δ8.84 (d, J=5.1Hz, 1H), 8.30 (d, J=2.1Hz, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.71 (d, J=2.1Hz, 1H), 7.65 (d, J=2.1Hz, 1H), 7.59 (dd, J=5.0, 3.3Hz, 1H), 7 .39 (d, J=8.4Hz, 2H), 7.20 (d, J=2.0Hz, 1H), 4.51 (t, J=6.8Hz, 2H), 4.42 (t, J=5.2Hz , 2H), 3.96 (t, J=5.2Hz, 2H), 3.33-3.27 (m, 2H), 1.69 (s, 6H), 1.67 (d, J=13.6Hz, 6H). 31 P NMR (162MHz, DMSO-d6) δ33.60 (s, 1P).

[0699] Example 111: Preparation of Compound 111

[0700] Preparation of compound 111-1

[0701] Compound 110-2 (2 g, 11.75 mmol) and triethylamine (3.6 g, 35.25 mmol) were dissolved in THF (20 mL). The system was cooled to 0°C and methanesulfonyl chloride (3.4 g, 29.38 mmol) was slowly added dropwise. The mixture was warmed to room temperature and stirred for 1 hour. LCMS monitored the reaction for completion. Ice water (20 mL) was added to quench the mixture and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase silica gel chromatography (PE / EA = 0-70%) to obtain 2.1 g of the title compound 111-1, in a 70% yield. LC-MS (ESI): m / z 153.1 [M+H] + .

[0702] Preparation of compound 111-2

[0703] Compound 111-1 (2 g, 8.05 mmol) and 4-bromopyridin-2(1H)-one (1.68 g, 9.66 mmol) were dissolved in 1,4-dioxane (20 mL). Cesium carbonate (2.23 g, 16.10 mmol) was added at room temperature and the mixture was heated to 90°C with stirring for 3 hours. LCMS monitoring revealed that the reaction was complete, quenched with ice water (20 mL), and extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by silica gel column chromatography (EA / PE = 0-100%) to obtain 1.4 g of the title compound 111-2 in a 50% yield. LC-MS (ESI): m / z 326.0 [M+H] + .

[0704] Preparation of compound 111-3

[0705] Compounds 12-3 (1.00 g, 2.17 mmol) and 111-2 (0.78 g, 2.39 mmol) were dissolved in 1,4-dioxane (15 mL). [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (0.16 g, 0.22 mmol) and aqueous potassium carbonate (2 mol / L, 3.3 mL, 6.51 mmol) were added. The atmosphere was replaced with argon four times and heated to 110°C with stirring for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched with water (30 mL). The mixture was filtered through a pad of Celite, and the filter cake was rinsed with ethyl acetate (50 mL). The filtrates were combined and extracted three times with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (MeOH / DCM = 0-5%) to obtain 1 g of the title compound 111-3 (yield 64%). LC-MS (ESI): m / z 578.9 [M+H] + .

[0706] Preparation of compound 111-4

[0707] Compound 111-3 (200.00 mg, 0.35 mmol) was dissolved in tetrahydrofuran (2 mL) and water (2 mL) solvent, potassium persulfate (0.86 g, 1.40 mmol) was added, and the mixture was stirred at room temperature for 16 hours. LCMS monitored the reaction to be complete. The reaction was quenched with water (5 mL) and extracted with ethyl acetate (10 mL) three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrates were combined and concentrated. The resulting residue was purified by preparative TLC to give 50 mg of the title compound 111-4 in a yield of 24%. LC-MS (ESI): m / z 611.1 [M+H] + .

[0708] Preparation of compound 111

[0709] Compound 111-4 (250 mg, 0.041 mmol) and dimethylphosphine oxide (16 mg, 0.21 mmol) were dissolved in acetonitrile (1 mL). Potassium carbonate (17 mg, 0.12 mmol) was added at room temperature and the mixture was heated to 85°C with stirring for 16 hours. LCMS monitored the reaction for completion. The mixture was cooled to room temperature, filtered through a pad of Celite, and rinsed with acetonitrile (5 mL). The filtrates were combined, concentrated, and purified by preparative TLC to afford the crude product, which was then purified by reverse-phase prep-HPLC (Waters 2767 / Qda, Column: Sunfire C18 19*250 mm, 10 μm; Mobile Phase A: 0.1% FA / H2O, Phase B: ACN; flow rate: 20 ml / min; gradient: 51% to 51%; Retention Time: 7.4-8.5 min of 16 min) to afford 2.7 mg of the title compound 111. LC-MS (ESI): m / z 609.3 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ8.71 (s, 1H), 7.50 (d, J = 8.3Hz, 2H), 7.45 (d, J = 2.3Hz, 1H), 7.37 (d, J = 7.1Hz, 1H), 7.33 (d, J = 2.3Hz, 1H), 7.26-7.22 (m, 3H), 6.77 (s, 1H), 6.37 (d, J=6.7Hz, 1H), 4.50-4.40 (m, 4H), 3.87 (t, J =6.1Hz, 2H), 3.41 (t, J = 6.1Hz, 2H), 1.88 (d, J = 13.5Hz, 6H), 1.68 (s, 6H). 31 P NMR (162MHz, CDCl3) δ35.24 (s, 1P).

[0710] Examples 112 and 113: Preparation of Compounds 112 and 113

[0711] Preparation of compound 112-1

[0712] 2-Hydroxy-5-bromobenzaldehyde (3 g, 14.59 mmol) was dissolved in toluene (90 mL). Ethylene glycol (2.8 g, 44.77 mmol) and p-toluenesulfonic acid (257 mg, 1.49 mmol) were added. The reaction system was heated to 160°C and stirred for 6 hours. LCMS monitored the reaction completion. The system was cooled to room temperature and quenched with ice water (50 mL). Extraction was performed three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase silica gel chromatography (EA / 0.1% TEA + PE = 0-30%) to obtain 1.6 g of the title compound 112-1 in a 44% yield. LC-MS (ESI): m / z 244.7 [MH] - .

[0713] Preparation of compound 112-2

[0714] Compound 12-3 (400 mg, 0.87 mmol), compound 112-1 (213 mg, 0.87 mmol), Pd(dppf)Cl2 (64 mg, 0.087 mmol), and potassium carbonate (361 mg, 2.61 mmol) were dissolved in dioxane (15 mL), replaced with argon, and heated to 110°C with stirring for 2 hours. LCMS monitored the reaction completion. The system was cooled to room temperature, filtered through a pad of Celite, and rinsed with ethyl acetate. The filtrates were combined and concentrated, and the resulting residue was purified by silica gel chromatography (EA / 0.1% TEA + PE = 0-50%) to afford 200 mg of the title compound 112-2, in a 50% yield. LC-MS (ESI): m / z 495.8 [MH] - .

[0715] Preparation of compound 112-3

[0716] Compound 112-2 (800 mg, 1.60 mmol) and 2-chloro-4-(chloromethyl)pyrimidine (286 mg, 1.77 mmol) were dissolved in acetonitrile (8 mL). Cesium carbonate (1.6 g, 4.8 mmol) was added at room temperature and the mixture was heated to 70°C and stirred for 2 hours. LCMS monitored the reaction for completion. The mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate. The filtrates were combined and concentrated, and the resulting residue was purified by silica gel column chromatography (EA / PE = 0-50%) to give 760 mg of the title compound 112-3 in a yield of 76%. LC-MS (ESI): m / z 624.1 [M+3] + .

[0717] Preparation of compound 112-4

[0718] Compound 112-3 (760 mg, 1.22 mmol) and dimethylphosphine oxide (380 mg, 4.88 mmol) were dissolved in DMF (7 mL). Palladium acetate (27 mg, 0.12 mmol), 1,3-bis(diphenylphosphino)propane (50 mg, 0.12 mmol), and DIPEA (790 mg, 6.1 mmol) were added at room temperature. The atmosphere was replaced with argon three times. The reaction was stirred and stirred at 120°C for 30 minutes. LCMS analysis confirmed the reaction was complete. Water (30 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (MeOH / DCM = 0-10%) to afford 800 mg of the title compound 112-4 in a 98% yield. LC-MS (ESI): m / z 666.1 [M+H] + .

[0719] Preparation of compound 112-5

[0720] Compound 112-4 (800 mg, 1.2 mmol) was dissolved in tetrahydrofuran (5 mL), and hydrochloric acid (4 mL, 1 M) was added at room temperature. The mixture was stirred at room temperature for 2 hours. LCMS monitored the reaction completion. Aqueous solution (30 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). The mixture was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (MeOH / DCM = 0-15%) to afford 356 mg of the title compound 112-5, in a yield of 48%. LC-MS (ESI): m / z 622.1 [M+H] + .

[0721] Preparation of compound 112

[0722] Compound 112-5 (356 mg, 0.57 mmol) was dissolved in tert-butanol (5 mL) and water (1 ml). Sodium chlorite (64 mg, 0.71 mmol), sodium dihydrogen phosphate (680 mg, 5.7 mmol), and 2-methyl-2-butene (400 mg, 5.7 mmol) were added at room temperature and stirred for 16 hours. The reaction was complete when monitored by LCMS. Saturated brine (30 mL) was added and the mixture was extracted three times with ethyl acetate (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (MeOH / DCM = 0-15%) to obtain 300 mg of the title compound 112. LC-MS (ESI): m / z 636.0 [MH] + . 1H NMR (400MHz, DMSO-d6) δ9.00 (d, J=5.1Hz, 1H), 8.10-8.02 (m, 1H), 7.84 (s, 1H), 7.71 (d, J=2.1Hz, 1H), 7.68-7.59 (m, 2H), 7.56 (d, J=8.2Hz, 2H) , 7.31 (d, J = 8.2Hz, 2H), 7.20 (d, J = 8.7Hz, 1H), 5.37 (s, 2H), 4.42 (t, J = 5.2Hz, 2H), 3.96 (t, J = 5.2Hz, 2H), 1.77 (d, J = 13.7Hz, 6H), 1.68 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.48 (s, 1P).

[0723] Preparation of compound 113

[0724] Compound 112 (50 mg, 0.078 mmol) was dissolved in DMF (1 mL) and ammonium chloride (6.3 mg, 0.12 mmol), HATU (44 mg, 0.12 mmol), and DIPEA (30 mg, 0.23 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was monitored for completion by LCMS. The product was then purified by preparative HPLC (Waters 2767 / Qda, Column: XBridge C18 19*250 mm, 10 μm; Mobile phase A: 0.1% TFA / H2O, Mobile phase B: acetonitrile; Flow rate: 20 mL / min; Elution gradient: 55%-65%; Retention time: 8.0-9.2 min of 16 min) to afford 6 mg of the title compound 113. LC-MS (ESI): m / z 637.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.01 (d, J=5.2Hz, 1H), 8.00 (d, J=2.5Hz, 1H), 7.98 (s, 1H), 7.77 (dd, J=5.1, 3.2Hz, 1H), 7.74 (dd, J=8.6, 2.5Hz, 1H), 7.70 (d, J=2.3Hz, 1H), 7.64 (d, J=2 .3Hz, 2H), 7.59 (d, J=8.4Hz, 2H), 7.33 (d, J=8.4Hz, 2H), 7.26 (d, J=8.8Hz, 1H), 5.50 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 1.76 (d, J=13.7Hz, 6H), 1.69 (s, 6H). 31P NMR (162MHz, DMSO-d6) δ34.02 (s, 1P).

[0725] Example 114: Preparation of Compound 114

[0726] Preparation of Compound 114

[0727] Compound 112 (50 mg, 0.078 mmol) was dissolved in DMF (1 mL). Methylamine hydrochloride (7.9 mg, 0.12 mmol), HATU (44 mg, 0.12 mmol), and DIPEA (30 mg, 0.23 mmol) were added at room temperature and stirred for 2 hours. The reaction was monitored for completion by LCMS. The filtrate was filtered and purified by reverse phase preparative HPLC (Preparative HPLC: Waters 2767 / Qda, separation column: XBridge XBridge C18 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; elution gradient: 59% to 69%; retention time: 7.4-8.6 min of 16 min) to obtain 16.4 mg of the title compound 114. LC-MS (ESI): m / z 651.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.02 (d, J=5.2Hz, 1H), 8.40 (q, J=4.7Hz, 1H), 7.93 (d, J= 2.4Hz, 1H), 7.78-7.68 (m, 3H), 7.64 (d, J=2.3Hz, 1H), 7.59 (d, J=8.4Hz, 2H), 7.3 3 (d, J=8.4Hz, 2H), 7.25 (d, J=8.7Hz, 1H), 5.49 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 3. 96 (t, J=5.2Hz, 2H), 2.87 (d, J=4.6Hz, 3H), 1.76 (d, J=13.7Hz, 6H), 1.69 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.01 (s, 1P).

[0728] Example 115: Preparation of Compound 115

[0729] Preparation of compound 115

[0730] Compound 112 (50 mg, 0.078 mmol) was dissolved in DMF (1 mL). Dimethylamine hydrochloride (9.5 mg, 0.12 mmol), HATU (44 mg, 0.12 mmol), and DIPEA (30 mg, 0.23 mmol) were added at room temperature and stirred for 2 hours. LCMS monitored the reaction for completion. The reaction solution was filtered, and the filtrate was purified by reverse phase chromatography (Waters 2767 / Qda, XBridge C18 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 59% to 69%; retention time: 8.0-8.8 min of 16 min) to afford 9.6 mg of the title compound 115. LC-MS (ESI): m / z 665.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.03 (d, J=5.2Hz, 1H), 7.73-7.66 (m, 2H), 7.63 (d, J=2.3Hz, 1H), 7.62-7.57 (m, 3H), 7.52 (d, J=2.3Hz, 1H), 7.31 (d, J=8.5Hz, 2H), 7.23 (d, J=8.8Hz, 1H), 5.41 (s, 2H), 4.42 (t, J=5.2Hz, 2H), 3.96 (t, J= 5.2Hz, 2H), 3.05 (s, 3H), 2.86 (s, 3H), 1.76 (d, J=13.7Hz, 6H), 1.68 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ33.99 (s, 1P).

[0731] Example 116: Preparation of Compound 116

[0732] Preparation of Compound 116

[0733] Compound 112-5 (100 mg, 0.16 mmol) was dissolved in methanol (5 mL) and sodium borohydride (24 mg, 0.643 mmol) was added at room temperature. The reaction was stirred at room temperature for 2 hours. LCMS monitored the reaction for completion. The residue was then dried and purified by reverse phase chromatography (Waters 2767 / Qda, XBridge C18 19*250 mm, 10 μm; mobile phase A: 0.1% FFA / H2O, mobile phase B: ACN; flow rate: 20 ml / min; gradient: 50% to 59%; retention time: 7.0-8.0 min of 16 min) to yield 20.2 mg of the title compound 116. LC-MS (ESI): m / z 624.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.01 (d, J=5.1Hz, 1H), 7.77-7.73 (m, 1H), 7.72-7.68 (m, 2H ), 7.63 (d, J = 2.1Hz, 1H), 7.56 (d, J = 8.2Hz, 2H), 7.50 (d, 1H), 7.32 (d, J = 8.3Hz, 2H) , 7.09 (d, J = 8.6Hz, 1H), 5.36 (s, 2H), 5.17 (t, J = 5.7Hz, 1H), 4.70 (d, J = 5.6Hz, 2H), 4.42 (t, J=5.2Hz, 2H), 3.96 (t, J=5.2Hz, 2H), 1.77 (d, J=13.7Hz, 6H), 1.69 (s, 6H). 31 P NMR (162MHz, DMSO-d6) δ34.00 (s, 1P).

[0734] Example 117: Preparation of Compound 117

[0735] Preparation of compound 117-1

[0736] Compound 12-3 (500 mg, 1.09 mmol) and 2-fluoro-4-bromophenol (250 mg, 1.31 mmol) were dissolved in 1,4-dioxane (8 mL). Pd(dppf)Cl2 (80 mg, 0.11 mmol) and aqueous potassium carbonate (2 mol / L, 1.6 mL, 3.27 mmol) were added. The atmosphere was purged with argon four times and heated to 110°C with stirring for 3 hours. LCMS confirmed the reaction was complete and the mixture was cooled to room temperature. The pH was adjusted to acidic with 2 mol / L aqueous hydrochloric acid, filtered through a pad of Celite, and the filter cake was rinsed with ethyl acetate (30 mL). The filtrates were combined, washed once with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and...

Claims

1. A compound represented by formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof, in, R1 is selected from H, halogen, OH, CN, NH2, H2N-S(=O)2-, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)(=NH)-, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)(=NH)-, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R; R2, R3, and R4 are independently selected from H, CN, F, Cl, Br, OH, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-, C 2-6 Alkenyl-O-, C 2-6 Alkenyl-S-, C 2-6 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S- or 4-6 membered heterocycloalkyl-NH-, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-, C 2-6 Alkenyl-O-, C 2-6 Alkenyl-S-, C 2-6 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3- 6-cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S- and 4-6 membered heterocycloalkyl-NH- are optionally substituted with 1, 2 or 3 R; R5, R6, and R7 are independently selected from H, CN, F, Cl, Br, OH, NH2, C(=O)OH, C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-, C 2-6 Alkenyl-O-, C 2-6 Alkenyl-S-, C 2-6 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S-, 4-6 membered heterocycloalkyl-NH-, C 6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocycloalkyl, the C(=O)OCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-, C 2-6 Alkenyl-O-, C 2-6 Alkenyl-S-, C 2-6 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S-, 4-6 membered heterocycloalkyl-NH-, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R; m, n, y are independently selected from 0, 1, 2, 3 or 4; L1 is selected from a single bond, -NH-, =N-, -O-, -C≡C-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -CH2-, -CH2CH2-, -OCH2-, C 3- 6-membered cycloalkyl or 3-10-membered heterocycloalkyl, wherein the -NH-, -CH2-, -CH2CH2-, -OCH2-, C 3-6 Cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1 or 2 R; Selected from And when Selected from When L1 is selected from =N- or 3-10 membered heterocycloalkyl; L2 is selected from a single bond, -C≡C-, -CH=CH-, -(CR8R9)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR 10 -、-C 1-3 Alkyl-O-, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, the -C 1-3 Alkyl-O-, C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2 or 3 R; L3 is selected from a single bond, -C≡C-, -CH=CH-, -(CR8R9)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NR 10 -or-C 1-3 Alkyl-O-, the-C 1-3 Alkyl-O- is optionally substituted with 1, 2 or 3 R; Furthermore, L2 and L3 are not simultaneously selected from single bonds; And, when L2 is selected from C 3-6 Cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 When aryl or 5-10 membered heteroaryl, L3 is not selected from a single bond; L4 is selected from -(CR8R9)x-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2- or -NR 10 -; R8 and R9 are independently selected from H, CN, F, Cl, Br, OH, NH2, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R; R 10 Select from H or C 1-6 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 heteroalkyl or 3-10 membered heterocycloalkyl, the C 1- 6 alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, C 1-6 Heteroalkyl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R; x is selected from 1, 2 or 3; Ring A is selected from C 4-10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl or 5-10 membered heteroaryl; Ring B, Ring C, and Ring D are independently selected from C 4-10 Cycloalkyl, 4-10 membered heterocycloalkyl, phenyl, 5-10 membered heteroaryl, benzo 5-6 Cycloalkyl, benzo 5-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C 5-6 Cycloalkyl or 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl; R is independently selected from H, halogen, =O, =NR', OH, NH2, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkyl-S(=O)2-, (C 1-6 alkyl)2-P(=O)-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-OC(=O)-, C 1- 6-alkyl-C(=O)NH-, C 1-6 Alkyl-NH-C(=O)-, C 1-6 Alkyl-S(=O)NH-, C 1-6 Alkyl-S(=O)2NH-, C 1-6 Alkyl-NHS(=O)2-, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-, C 2-6 Alkenyl-O-, C 2-6 Alkenyl-S-, C 2-6 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3- 6-cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, C 3-6 Cycloalkyl-C(=O)-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S-, 4-6 membered heterocycloalkyl-NH- or C 6-10 Aryl-C 1-6 Alkyl-, the C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-6 Alkyl-S(=O)2-, (C 1-6 alkyl)2-P(=O)-, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)O-, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-C(=O)NH-, C 1-6 Alkyl-NH-C(=O)-, C 1-6 Alkyl-S(=O)NH-, C 1-6 Alkyl-S(=O)2NH-, C 1-6 Alkyl-NHS(=O)2-, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1- 6-alkyl-NH-, C 2-6 Alkenyl-O-, C 2-6 Alkenyl-S-, C 2-6 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, C 3-6 Cycloalkyl-C(=O)-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S-, 4-6 membered heterocycloalkyl-NH- or C 6-10 Aryl-C 1-6 Alkyl - optionally substituted with 1, 2 or 3 R'; R' is selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, CH2F, CHF2, CF3 and C 1-6 Alkyl-S(=O)2-; the above heteroaryl, heteroalkyl or heterocycloalkyl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C(=O), C(=O)O, C(=O)NH, S(=O), S(=O)2, P(=O), S(=O)2NH and N.

2. The compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from H, halogen, OH, NH2, CN, =O、=NR'、C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-S(=O)2-, (C 1-3 alkyl)2-P(=O)-, C 1-3 Alkyl-C(=O)O-, C 1-3 Alkyl-OC(=O)-, C 1-3 Alkyl-C(=O)NH-, C 1-3 Alkyl-NH-C(=O)-, C 1-3 Alkyl-S(=O)NH-, C 1-3 Alkyl-S(=O)2NH-, C 1-3 Alkyl-NHS(=O)2-, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-NH-, C 3-6 Cycloalkyl-C(=O)-, 4-6 membered heterocycloalkyl-O-, 4-6 membered heterocycloalkyl-S-, 4-6 membered heterocycloalkyl-NH- or C 6-10 Aryl-C 1-3 Alkyl-, the C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-S(=O)2-, (C 1-3 alkyl)2-P(=O)-, C 1-3 Alkyl-C(=O)O-, C 1-3 Alkyl-OC(=O)-, C 1-3 Alkyl-C(=O)NH-, C 1-3 Alkyl-NH-C(=O)-, C 1-3 Alkyl-S(=O)NH-, C 1-3 Alkyl-S(=O)2NH-, C 1-3 Alkyl-NHS(=O)2-, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-NH-, C 3- 6-membered cycloalkyl-C(═O)-, 4-6-membered heterocycloalkyl-O-, 4-6-membered heterocycloalkyl-S-, 4-6-membered heterocycloalkyl-NH- or C 6-10 Aryl-C 1-3 Alkyl- or C 6- 10 Aryl-C 1-3 Alkyl- is optionally substituted with 1, 2 or 3 R'.

3. The compound according to claim 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from H, F, Cl, Br, I, OH, NH2, CN, =O, =NH, =N-CN, CH3, CH2F, CHF2, CF3, 4. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from H, halogen, OH, CN, NH2, H2N-S(=O)2-, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-S(=O)2-, (C 1-6 alkyl)2-S(=O)=, (C 1-6 alkyl)2-P(=O)-, (C 1-6 alkyl)2-S(=O)=N-, C 1-6 Alkyl-S(=O)2NH-, C 1-6 Alkyl-NHS(=O)2-, C 1-6 Alkyl-NH-, C 1-6 Alkyl-S(=O)(=NH)-, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)(=NH)-, C 6-10 aryl, 5-10 membered heteroaryl or 3-10 membered heterocycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-O-, C 1-6 Alkyl-S-, C 1-6 Alkyl-S(=O)2-, (C 1-6 alkyl)2-S(=O)=, (C 1-6 alkyl)2-P(=O)-, (C 1-6 alkyl)2-S(=O)=N-, C 1-6 Alkyl-S(=O)2NH-, C 1-6 Alkyl-NHS(=O)2-, C 1-6 Alkyl-NH-, C 1-6 Alkyl-S(=O)(=NH)-, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, C 3-6 Cycloalkyl-S(=O)2-, C 3-6 Cycloalkyl-S(=O)(=NH)-, C 6-10 Aryl, 5-10 membered heteroaryl and 3-10 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R groups.

5. The compound according to claim 4, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from H, F, Cl, Br, I, Me, CN, OH, NH2, H2N-S(=O)2-, Said Optionally substituted with 1, 2 or 3 R.

6. The compound according to claim 5, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from H, F, Cl, Br, I, Me, CN, OH, NH2, H2N-S(=O)2-, 7. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: L1 is selected from a single bond, -CH2-, -NH-, =N-, -O-, -C≡C-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, 8. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from H, F, Cl, Br, I, H2N-S(=O)2-, 9. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R2, R3, and R4 are independently selected from H, CN, F, Cl, Br, OH, NH2, C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-NH-, C 2-3 Alkenyl-O-, C 2-3 Alkenyl-S-, C 2-3 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, oxirane-O- or azetidinyl-O-, the C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-NH-, C 2-3 Alkenyl-O-, C 2-3 Alkenyl-S-, C 2-3 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH-, oxirane-O- and azetidinyl-O- are optionally substituted with 1, 2 or 3 R groups.

10. The compound according to claim 9, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R2, R3, and R4 are independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me, The Me, Optionally substituted with 1, 2 or 3 R.

11. The compound according to claim 10, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R2, R3, and R4 are independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me, 12. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R5, R6, and R7 are independently selected from H, CN, F, Cl, Br, OH, NH2, -COOH, -COOCH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-NH-, C 2-3 Alkenyl-O-, C 2-3 Alkenyl-S-, C 2-3 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH- or oxirane-O-, the C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Alkyl-S-, C 1-3 Alkyl-NH-, C 2-3 Alkenyl-O-, C 2-3 Alkenyl-S-, C 2-3 Alkenyl-NH-, C 3-6 Cycloalkyl-O-, C 3-6 Cycloalkyl-S-, C 3-6 Cycloalkyl-NH- and oxirane-O- are optionally substituted with 1, 2 or 3 R groups.

13. The compound according to claim 12, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R5, R6, and R7 are independently selected from H, CN, F, Cl, Br, OH, NH2, CN, Me, CH2F, CHF2, CF3, COOH, -COOMe, 14. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R8 and R9 are independently selected from H, CN, F, Cl, Br, OH, NH2, Me or 15. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R 10 Selected from H, Me, 16. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: L2 is selected from a single bond, -CH2-, -CH(CH3)-, -OCH2-, -C≡C-, -CH=CH-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NH-, 17. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: L3 is selected from a single bond, -CH2-, -CH(CH3)-, -OCH2-, -C≡C-, -CH=CH-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2- or -NH-.

18. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: L2-L3 is selected from -CH2-, -CH2CH2-, -CH(CH3)-, -C≡C-, -CH=CH-, -O-, -OCH2-, -OCH2CH2-, -OCH(CH3)-, -OCH2OCH2-, -OCH2CH2O-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, -NH-, -CH2NH-, 19. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: L4 is selected from -CH2-, -O-, -S-, -C(=O)-, -S(=O)-, -S(=O)2-, -NH-, 20. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, thienyl, oxazolyl, pyridazinyl, cyclobutanyl, oxetanyl, tetrahydropyranyl, 2-oxaspiro[3.3]heptane, 2-thia-6-azaspiro[3.3]heptane-2,2-dioxide, tetrahydrofuranyl, azetidinylpiperidinyl, 1,1-dioxidethiomorpholinyl, 2-thio-6-azaspiro[3.3]heptane-2,2-dioxyl, 2-imino-2λ6-thiaspiro[3.3]heptane 2-oxide, cyclohexanyl or 1-imino-1λ6-thiomorpholine 1-oxide.

21. The compound according to claim 20, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 22. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from a bicyclic [ 1.1.1]pentanyl, cyclobutanyl, cyclopentanyl, 2,6-diazaspiro[3.3]heptanyl, pyrazolyl, piperidinyl, thiazolyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, benzocyclopentanyl, benzocyclohexanyl, 1,2,3,4-tetrahydroquinolinyl, naphthyl, indolyl, isoindolyl, spiro[cyclopropane-1,3′-dihydroindole]-2′-onyl, 3(2H)-pyridazinonyl, 2(1H)-pyridinonyl, isoquinolinyl or quinolin-2(1H)-onyl.

23. The compound according to claim 22, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 24. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from azetidinyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl or spiro[cyclopropane-1,3'-dihydroindole]-2'-onyl.

25. The compound according to claim 24, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 26. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Ring D is selected from phenyl, pyridyl, benzocyclopentyl, benzocyclohexyl, 1H-indazolyl, 2H-indazolyl or 1H-benzo[d]imidazolyl.

27. The compound according to claim 11 or 26, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 28. A compound of the following formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:

29. Use of the compound according to any one of claims 1 to 28, its optical isomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with androgen receptor (AR) activity or expression.

30. The disease associated with androgen receptor (AR) activity or expression according to claim 29, selected from prostate cancer, ovarian cancer, breast cancer, bladder cancer, pancreatic cancer, endometrial cancer, hepatocellular carcinoma, renal cell carcinoma, melanoma, mantle cell lymphoma, glioblastoma, salivary gland cancer, alopecia, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy and age-related maculopathy.

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